Patent Publication Number: US-2020291353-A1

Title: Method for producing cell flaps

Description:
FIELD OF THE INVENTION 
     The present invention refers to an in vitro or ex vivo method for producing a flap of genetically modified cells on fibrin substrate and the flap so obtained. 
     BACKGROUND ART 
     To date, the procedure for the preparation of ex vivo genetically modified epidermis flaps involves the culture of cells on plastic supports with the aim of obtaining a genetically modified flap of the epidermis. The procedure described to date, for example in Mavilio et al. 2006 (12)  and Bauer et al. 2017 (10) , consists in plating, on plastic supports of 75-175 cm 2 , keratinocytes genetically corrected on feeder layers and allowing them to grow and reach full confluence (9-14 days). The attainment of the confluence represents a fundamental step to ensure the stability of the flap ( FIG. 1 ). The reason is due to the intrinsic stratification/differentiation process in keratinocytes, which, once they reach the confluence, slow down their proliferation in favor of stratification/differentiation processes. The stratification process ensures greater stability and compactness on the flap of the epidermis so formed, thus ensuring better maneuverability, a condition necessary for the assembly and transportation phases. Upon reaching the confluence ( FIG. 1 ), the epidermis flap is washed with a solution containing DMEM, L-Glutamine. Subsequently, the flap is dissociated from the plastic support by the addition of Dispase II (2.5 mg/ml). On the upper side (opposite to the one adhering to plastic) a Vaseline® Petrolatum gauze of 50 cm 2  is applied, which will be fixed to the epidermis flap by clips. Once the flap is secured, this is transferred to a transport flap container (or transportation box) ( FIG. 2 ). 
     The method for obtaining a flap starting from a plastic support is a long and complicated procedure. There are several steps that may invalidate the release of the same. The following table show the main steps that may lead to the non-conformity of the flap and to the loss of release (Table 1). 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 Parameters of non-conformity in releasing the flap. 
               
            
           
           
               
               
            
               
                   
                 Not 
               
               
                 Parameters 
                 conform 
               
               
                   
               
               
                 No conform evaluation of culture confluence before detachment 
                 x 
               
               
                 Presence of breaks after DISPASE detachment 
                 x 
               
               
                 Presence of breaks after application of gauzes and clips 
                 x 
               
               
                 Presence of bubbles in the transportation box 
                 x 
               
               
                 Presence of breaks during shipment 
                 x 
               
               
                 Presence of breaks after the transportation box opening 
                 x 
               
               
                   
               
            
           
         
       
     
     Regardless of the procedure used for preparing the flap, another step that can be a cause of failure to release the flap is its breakup during the transportation phases. Although the flap is secured and locked on the gauze, unintentional movements during transport may cause its breakage or the winding on itself. In case of breakage, the flap is considered to be inadequate (Table 1). 
     The procedure described above is not intuitive and without risk. In fact, in the setup phases, given the multiple steps and continuous manipulations, the risk of contamination or the presence of air bubbles, which can alter the O 2  exchange, may result in poor product quality. It is also known that keratinocytes in the absence of adhesion induce the activation of terminal differentiation processes (Watt F M, Jordan P W, O&#39;Neill C H. 1988. Cell shape controls terminal differentiation of human epidermal keratinocytes. Proc Natl Acad Sci USA 85:5576-5580), in fact, the stability of the genetically modified flap generated from plastic supports is 24 h. The biological quality as well as the performance of the flap so produced are remarkably reduced after 24 hours. Therefore, is still felt the need of an alternative method for providing genetically modified flaps wherein the cells are not subjected to an accelerated terminal differentiation due to the loss of contact with the substrate which usually happens in the previous disclosed conditions. 
     The patent application WO2005028638 refers to a process for producing a cell sheet, comprising culturing cells up to a state of saturation on the surface of a support having its surface coated with fibrin, continuing the culturing for a period of time sufficient to achieve decomposition of the fibrin at cell bottom surface and detaching the cultured cells in the form of a sheet from the support surface. Therefore, the patent application WO2005028638 teaches to obtain a sheet of cells not genetically modified, wherein the fibrin is not present because it was previously degraded. 
     A paper published by Pellegrini et al. in 1999, show the potential use of a matrix of fibrin for culturing human epithelial stem cells. Said publication shows that the culture of human keratinocytes on fibrin doesn&#39;t alter the biological properties of the cells and maintains their characteristic of staminality, as demonstrated by the presence of isolated holoclones in these conditions (epidermal stem cells) (Gallico, G. G., 3rd, et al. Permanent coverage of large burn wounds with autologous cultured human epithelium. The New England journal of medicine 311, 448-451 (1984); Pellegrini, G. et al. The control of epidermal stem cells (holoclones) in the treatment of massive full-thickness burns with autologous keratinocytes cultured on fibrin. Transplantation 68, 868-879 (1999); Cuono C. et al. Use of cultured epidermal autografts and dermal allografts as skin replacement after burn injury. Lancet 1:1123-1124 (1986); De Luca M, et al. 1989. Multicentre experience in the treatment of burns with autologous and allogenic cultured epithelium, fresh or preserved in a frozen state. Burns 15:303-309). In 2010, another work was published that demonstrates the clinical effectiveness of transplant of Corneal limbal cells in the treatment of severe burns by corneal epithelium (Rama P, Matuska S, Paganoni G, Spinelli A, De Luca M, Pellegrini G. 2010. Limbal stem-cell therapy and long-term corneal regeneration. N Engl J Med 363:147-155). In both papers, the epithelium was cultivated on a fibrin matrix starting from raw materials (fibrinogen and thrombin) produced, for example, by Baxter (Tissucol). This fibrin has been used in more than 200 epithelial corneal cell transplants, none of which has been found to have any adverse events due to rejection or inflammation. Preferably, the fibrin matrix is produced by Holostem Terapie Avanzate, from raw materials (fibrinogen and thrombin) produced for example by Kedrion. A comparative study performed on corneal limbal epithelial cells showed the equivalence of the two products (Table 2). 
     
       
         
           
               
               
               
               
               
             
               
                   
                 TABLE 2 
               
             
            
               
                   
                   
               
               
                   
                 lots of TISSUCOL 
                   
                 lots of KEDRION 
                   
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 parameter 
                 average 
                 dev stand. 
                 average 
                 dev stand. 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 % CFE 
                 19.1 
                 8.1 
                 17.6 
                 7.9 
               
               
                   
                 % Ab 
                 14.3 
                 4.3 
                 20.6 
                 12.3 
               
               
                   
                 % K3 
                 86.9 
                 2.4 
                 86.7 
                 5.4 
               
               
                   
                 % K19 
                 15.5 
                 16.3 
                 52.7 
                 25.8 
               
               
                   
                 % p63 
                 1.3 
                 0.9 
                 2.2 
                 1 
               
               
                   
                   
               
            
           
         
       
     
     Table 2. Resumes the results obtained from a comparative study carried out starting from different fibrin lots, using excipients (fibrin and fibrinogen) produced by Baxter (Tissucol) and by Kedrion. The results obtained show the equivalence of both products, as evidenced by chlonogenic values (% CFE) almost unchanged and by the value of the percentage of p63 positive cells superior when using excipients from Kedrion. 
     The potential use of a fibrin substrate for culturing cells is therefore already described. However, its use as a substrate for culturing genetically modified cells was not previously disclosed. 
     It is still felt the need of a method which allows to obtain a flap of genetically modified cells which overcomes the disadvantages of methods which require cell culture on plastic supports. 
     SUMMARY OF THE INVENTION 
     The present inventors have developed a method which uses fibrin for the production of genetically modified cell flaps. In a preferred aspect of the invention, the method comprises plating genetically corrected keratinocytes and feeder layer on a matrix (or substrate) of fibrin of size of 144 cm 2 . Unlike the production process of the epidermis flaps on plastic supports, the keratinocytes cultivated under these conditions do not have to reach full confluence, but the subconfluence to proceed with the preparation of this for transport ( FIG. 3 ). 
     Fibrin provides growth support to keratinocytes, both in the transport phase and before detaching from the support, thus securing a high proliferative/regenerative potential of the keratinocytes. 
     This prevents an accelerated differentiation process due to contact loss, found in the epidermis flap derived from growth in plastic (Table 1). During the transport phases, and after the detachment of the flap, (including cells, for example of epidermis, and fibrin), cells, particularly keratinocytes, will complete their growth and begin the in vivo layering/differentiation process. Despite the greater flexibility and handling of fibrin in the transport phase, it is still necessary to perform the compliance checks before the release of the flap. As shown in  FIG. 3 , holes in the fibrin or disomogeneity in the keratinocyte or feeder plating make the flap non-conforming to release. Fibrin is an ideal support for the growth of keratinocytes because it represents a compact and solid biodegradable biological matrix that ensures a great deal of maneuverability during preparation and transport phases. 
     The fibrin flap obtained is washed with a solution containing DMEM and L-Glutamine. Then, by means of sterile pliers, it is detached from the holder and placed in the transport container ( FIG. 4 ), where the transport medium will be added. The container is then sealed ensuring that no air bubble is present. The presence of bubbles would render the flap release not adequate for therapeutic applications, such as transplants ( FIG. 4 ). 
     Unlike the flap derived from growth on plastic, the fracture of the flap on the fibrin during the transport phases is a very rare event. 
     In addition, the performance and biological stability of the product are superior if compared to flap resulting from growth on plastic support. 
     In addition to this, the reduced risk of microbiological contamination due to the small number of manipulations required to set up the flap and the reduced risk of breakages in transport should also be taken into account. 
     The present invention thus allows to obtain cellular flaps from different cell types using the same procedure without any particular modification. In addition, this method allows to obtain a large number of flaps quickly and without the need to use expensive culturing plates. 
     DETAILED DESCRIPTION OF THE INVENTION 
     It is therefore an embodiment of the invention an in vitro method for producing a flap of genetically modified cells on fibrin substrate, characterized by:
         a) plating feeder cells on the upper surface of a fibrin substrate so as to obtain a fibrin substrate on which said feeder cells are adhered;   b) plating and cultivating to subconfluence said genetically modified cells on said fibrin substrate onto which feeder cells are adhered, said fibrin substrate being positioned on a solid support so that the cells do not interact with the surface of said support so as to obtain a flap of genetically modified cells adhered to said fibrin substrate;   c) detaching the flap of genetically modified cells adhered to said fibrin substrate from the support in a form similar to a sheet to obtain a flap of genetically modified cells on fibrin substrate.       

     Said solid support is preferably of plastic, e.g. a Petri dish, or of glass. 
     Preferably, said feeder cells are plated on the fibrin substrate from 2 to 24 hours before plating the genetically modified cells. 
     In a preferred embodiment of the invention, the method further comprises: before step c), the steps:
         b′) removing the culture medium and/or   b″) washing the flap of genetically modified cells adhered to said fibrin substrate with a washing solution   and/or after step c), the step of:   d) placing the obtained flap of genetically modified cells on fibrin substrate in a transport container.       

     The transport container preferably comprises a transport medium. 
     Said fibrin substrate has preferably dimensions of from about 0.32 cm 2  to about 300 cm 2 , preferably of about 31-144 cm 2 , more preferably of 144 cm 2 . 
     Preferably, said fibrin substrate comprises from about 20 to about 100 mg/ml of fibrinogen and from about 1 to about 10 IU/ml of thrombin. More preferably, said fibrin substrate comprises from about 20 to about 50 mg/ml of fibrinogen, preferably from about 20 to about 40 mg/ml of fibrinogen, and from about 3 to about 8 IU/ml of thrombin; even more preferably it comprises from about 20 to about 25 mg/ml of fibrinogen and from about 2 to about 4 IU/ml of thrombin. In a preferred aspect said fibrin substrate comprises about 23.1 mg/ml of fibrinogen and about 3.1 IU/ml of thrombin. 
     Preferably, said genetically modified cells are epithelial cells, preferably primary epithelial cells deriving from stratified epithelia, more preferably epidermal cells, preferably keratinocytes, more preferably human primary keratinocytes isolated from biopsies, preferably skin biopsies. Said genetically modified cells have preferably been transduced with a gene or a cDNA selected from the group consisting of: 
     a) at least one chain selected from the group consisting of: beta-3, α3 and γ2 chain of laminin-5, and/or 
     b) collagen 17 and/or 
     c) at least one α6β4 integrin and/or 
     d) collagen 7 and/or 
     e) keratin 5 and Keratin 14 and/or 
     f) Plectin. 
     Preferably, said genetically modified cells have preferably been transduced with a gene or a cDNA selected from the group consisting of: beta-3 chain of laminin 5, collagen 7 and collagen 17. 
     In a preferred embodiment, the gene or cDNA encode for the above-mentioned protein or for an amino acid sequence having at least 75% amino acid sequence identity to the amino acid sequence SEQ ID NO: 6 and/or to the amino acid sequence SEQ ID NO:4 and/or to the amino acid sequence SEQ ID NO: 2. 
     Another embodiment of the invention is a flap of genetically modified cells on fibrin substrate, obtainable by the above described method. 
     A further object of the invention is a flap of genetically modified cells on fibrin substrate, wherein said cells are preferably epithelial cells, preferably primary epithelial cells deriving from stratified epithelia, more preferably epidermal cells, preferably keratinocytes, even more preferably human primary keratinocytes isolated from biopsies, preferably skin biopsies. 
     Preferably said genetically modified cells are transduced with a gene or cDNA selected from the group consisting of: 
     a) at least one chain selected from the group consisting of: beta-3, α3 and γ2 chain of laminin-5, and/or 
     b) collagen 17 and/or 
     c) at least one a6134 integrin and/or 
     d) collagen 7 and/or 
     e) keratin 5 and Keratin 14 and/or 
     f) Plectin. 
     Preferably said genetically modified cells are transduced with a gene or cDNA selected from the group consisting of: beta-3 chain of laminin 5, collagen 7 and collagen 17. 
     In a preferred embodiment, the gene or cDNA encode for the above-mentioned protein or for an amino acid sequence having at least 75% amino acid sequence identity to the amino acid sequence SEQ ID NO: 6 and/or to the amino acid sequence SEQ ID NO:4 and/or to the amino acid sequence SEQ ID NO: 2. 
     Preferably, the genetically modified cells are cells that have been transduced with a retroviral vector, said retroviral vector preferably being an alpharetroviral vector, a gammaretroviral vector, a lentiviral vector or a spumaretroviral vector. 
     Preferably, said fibrin substrate comprises from about 20 to about 100 mg/ml of fibrinogen and from about 1 to about 10 IU/ml of thrombin. More preferably, said fibrin substrate comprises from about 20 to about 50 mg/ml of fibrinogen, preferably from about 20 to about 40 mg/ml of fibrinogen, and from about 3 to about 8 IU/ml of thrombin; even more preferably it comprises from about 20 to about 25 mg/ml of fibrinogen and from about 2 to about 4 IU/ml of thrombin. In a preferred aspect said fibrin substrate comprises about 23.1 mg/ml of fibrinogen and about 3.1 IU/ml of thrombin. 
     Another embodiment of the invention is the above described flap for medical use. 
     A further embodiment of the invention is the use of a solid support which surface is covered by a fibrin substrate for the preparation of flaps of genetically modified cells on fibrin substrate, preferably said fibrin substrate comprises from about 20 to about 100 mg/ml of fibrinogen and from about 1 to about 10 IU/ml of thrombin. More preferably, said fibrin substrate comprises from about 20 to about 50 mg/ml of fibrinogen, preferably from about 20 to about 40 mg/ml of fibrinogen, and from about 3 to about 8 IU/ml of thrombin; even more preferably it comprises from about 20 to about 25 mg/ml of fibrinogen and from about 2 to about 4 IU/ml of thrombin. In a preferred aspect said fibrin substrate comprises about 23.1 mg/ml of fibrinogen and about 3.1 IU/ml of thrombin. 
     In a preferred embodiment of the invention above disclosed, thawed genetically modified cells, in particular keratinocytes cells, and feeder cells may be plated at the same time. Alternatively, it is possible to plate feeder cells and after 2 h-24 h thawing the genetically modified cells, in particular keratinocytes. 
     In the context of the present invention “IU” refers to “International Unit”. 
     In a preferred embodiment of the present invention, the genetically modified cells are cells that have been transduced with a retroviral vector carrying the cDNA of (or the nucleotide sequence encoding for) the beta-3 chain of laminin 5. However, results similar to those herein shown were obtained with similar products (e.g. retroviral vectors carrying different genes). The retroviral vector may e.g. be an alpharetroviral vector, a gammaretroviral vector, a lentiviral vector or a spumaretroviral vector. 
     In the context of the present invention the “feeder cells” or “feeder” are preferably cells obtained according to the method disclosed in Rheinwald J G, Green H. 1975. Serial cultivation of strains of human epidermal keratinocytes: the formation of keratinizing colonies from single cells. Cell 6:331-343. 
     They correspond to a clone of murine cells isolated in the laboratory of prof. Green H. (Rheinwald, J. et al 1975). 
     With the term “flap of cells” or “cell flap” it is intended preferably a sheet of epithelial cells, comprising cells in a single layer or in multilayer able to recreate an epidermis ex vivo. 
     According to the present invention the fibrin substrate (or fibrin support) is preferably a fibrin gel which is obtainable by admixing fibrinogen and thrombin, thus obtaining a fibrinogen and thrombin composition or solution. 
     The step of detachment of the flap from the support in the method according to the present invention is preferably carried out by mechanical methods, e.g. using pliers or forceps. However, any method known by the skilled man may be used. 
     In the context of the present invention “similar to a sheet” is preferably intended as an intact cell sheet. 
     The term “comprises” when referred to the fibrin substrate can also be intended as “obtainable by admixing”. 
     The expression “genetically modified cells” includes cells comprising a heterologous nucleic acid, for example which were transduced or transfected with one or more nucleic acid. 
     Said heterologous nucleic acid is preferably at least one gene or cDNA (or a nucleotide sequence encoding for a polypeptide) selected from the group consisting of: beta-3 chain of laminin 5, collagen 7, collagen 17 or combination thereof. 
     The starting cell may be e.g. transduced or transfected with a construct that will be integrated in the cell genome in place of the target endogenous gene or in different regions, where said construct comprises a heterologous sequence of the gene of interest and in some cases also a selectable marker which allows to select the obtained genetically modified cells. Alternatively, the genetically modified cells may not comprise a sequence (also partial) of a particular nucleic acid encoding a specific protein or peptide, for example obtained by deletion of a genetic sequence. The washing solution used in the above method is preferably “Dulbecco&#39;s modified eagle medium (DMEM)”, supplemented with L-glutamine. The transport medium used in the above method is preferably “Dulbecco&#39;s modified eagle medium (DMEM)”, supplemented with L-glutamine. 
     Preferably, the collagen 7 is characterized by the sequence as disclosed in in the NCBI Data Bank with the Accession no.: NM_000094.3 (Col7A1). The cDNA sequence is: 
     
       
         
           
               
            
               
                 (SEQ ID NO: 1) 
               
               
                 ATGACGCTGCGGCTTCTGGTGGCCGCGCTCTGCGCCGGGATCCTGGCAGA 
               
               
                   
               
               
                 GGCGCCCCGAGTGCGAGCCCAGCACAGGGAGAGAGTGACCTGCACGCGCC 
               
               
                   
               
               
                 TTTACGCCGCTGACATTGTGTTCTTACTGGATGGCTCCTCATCCATTGGC 
               
               
                   
               
               
                 CGCAGCAATTTCCGCGAGGTCCGCAGCTTTCTCGAAGGGCTGGTGCTGCC 
               
               
                   
               
               
                 TTTCTCTGGAGCAGCCAGTGCACAGGGTGTGCGCTTTGCCACAGTGCAGT 
               
               
                   
               
               
                 ACAGCGATGACCCACGGACAGAGTTCGGCCTGGATGCACTTGGCTCTGGG 
               
               
                   
               
               
                 GGTGATGTGATCCGCGCCATCCGTGAGCTTAGCTACAAGGGGGGCAACAC 
               
               
                   
               
               
                 TCGCACAGGGGCTGCAATTCTCCATGTGGCTGACCATGTCTTCCTGCCCC 
               
               
                   
               
               
                 AGCTGGCCCGACCTGGTGTCCCCAAGGTCTGCATCCTGATCACAGACGGG 
               
               
                   
               
               
                 AAGTCCCAGGACCTGGTGGACACAGCTGCCCAAAGGCTGAAGGGGCAGGG 
               
               
                   
               
               
                 GGTCAAGCTATTTGCTGTGGGGATCAAGAATGCTGACCCTGAGGAGCTGA 
               
               
                   
               
               
                 AGCGAGTTGCCTCACAGCCCACCAGTGACTTCTTCTTCTTCGTCAATGAC 
               
               
                   
               
               
                 TTCAGCATCTTGAGGACACTACTGCCCCTCGTTTCCCGGAGAGTGTGCAC 
               
               
                   
               
               
                 GACTGCTGGTGGCGTGCCTGTGACCCGACCTCCGGATGACTCGACCTCTG 
               
               
                   
               
               
                 CTCCACGAGACCTGGTGCTGTCTGAGCCAAGCAGCCAATCCTTGAGAGTA 
               
               
                   
               
               
                 CAGTGGACAGCGGCCAGTGGCCCTGTGACTGGCTACAAGGTCCAGTACAC 
               
               
                   
               
               
                 TCCTCTGACGGGGCTGGGACAGCCACTGCCGAGTGAGCGGCAGGAGGTGA 
               
               
                   
               
               
                 ACGTCCCAGCTGGTGAGACCAGTGTGCGGCTGCGGGGTCTCCGGCCACTG 
               
               
                   
               
               
                 ACCGAGTACCAAGTGACTGTGATTGCCCTCTACGCCAACAGCATCGGGGA 
               
               
                   
               
               
                 GGCTGTGAGCGGGACAGCTCGGACCACTGCCCTAGAAGGGCCGGAACTGA 
               
               
                   
               
               
                 CCATCCAGAATACCACAGCCCACAGCCTCCTGGTGGCCTGGCGGAGTGTG 
               
               
                   
               
               
                 CCAGGTGCCACTGGCTACCGTGTGACATGGCGGGTCCTCAGTGGTGGGCC 
               
               
                   
               
               
                 CACACAGCAGCAGGAGCTGGGCCCTGGGCAGGGTTCAGTGTTGCTGCGTG 
               
               
                   
               
               
                 ACTTGGAGCCTGGCACGGACTATGAGGTGACCGTGAGCACCCTATTTGGC 
               
               
                   
               
               
                 CGCAGTGTGGGGCCCGCCACTTCCCTGATGGCTCGCACTGACGCTTCTGT 
               
               
                   
               
               
                 TGAGCAGACCCTGCGCCCGGTCATCCTGGGCCCCACATCCATCCTCCTTT 
               
               
                   
               
               
                 CCTGGAACTTGGTGCCTGAGGCCCGTGGCTACCGGTTGGAATGGCGGCGT 
               
               
                   
               
               
                 GAGACTGGCTTGGAGCCACCGCAGAAGGTGGTACTGCCCTCTGATGTGAC 
               
               
                   
               
               
                 CCGCTACCAGTTGGATGGGCTGCAGCCGGGCACTGAGTACCGCCTCACAC 
               
               
                   
               
               
                 TCTACACTCTGCTGGAGGGCCACGAGGTGGCCACCCCTGCAACCGTGGTT 
               
               
                   
               
               
                 CCCACTGGACCAGAGCTGCCTGTGAGCCCTGTAACAGACCTGCAAGCCAC 
               
               
                   
               
               
                 CGAGCTGCCCGGGCAGCGGGTGCGAGTGTCCTGGAGCCCAGTCCCTGGTG 
               
               
                   
               
               
                 CCACCCAGTACCGCATCATTGTGCGCAGCACCCAGGGGGTTGAGCGGACC 
               
               
                   
               
               
                 CTGGTGCTTCCTGGGAGTCAGACAGCATTCGACTTGGATGACGTTCAGGC 
               
               
                   
               
               
                 TGGGCTTAGCTACACTGTGCGGGTGTCTGCTCGAGTGGGTCCCCGTGAGG 
               
               
                   
               
               
                 GCAGTGCCAGTGTCCTCACTGTCCGCCGGGAGCCGGAAACTCCACTTGCT 
               
               
                   
               
               
                 GTTCCAGGGCTGCGGGTTGTGGTGTCAGATGCAACGCGAGTGAGGGTGGC 
               
               
                   
               
               
                 CTGGGGACCCGTCCCTGGAGCCAGTGGATTTCGGATTAGCTGGAGCACAG 
               
               
                   
               
               
                 GCAGTGGTCCGGAGTCCAGCCAGACACTGCCCCCAGACTCTACTGCCACA 
               
               
                   
               
               
                 GACATCACAGGGCTGCAGCCTGGAACCACCTACCAGGTGGCTGTGTCGGT 
               
               
                   
               
               
                 ACTGCGAGGCAGAGAGGAGGGCCCTGCTGCAGTCATCGTGGCTCGAACGG 
               
               
                   
               
               
                 ACCCACTGGGCCCAGTGAGGACGGTCCATGTGACTCAGGCCAGCAGCTCA 
               
               
                   
               
               
                 TCTGTCACCATTACCTGGACCAGGGTTCCTGGCGCCACAGGATACAGGGT 
               
               
                   
               
               
                 TTCCTGGCACTCAGCCCACGGCCCAGAGAAATCCCAGTTGGTTTCTGGGG 
               
               
                   
               
               
                 AGGCCACGGTGGCTGAGCTGGATGGACTGGAGCCAGATACTGAGTATACG 
               
               
                   
               
               
                 GTGCATGTGAGGGCCCATGTGGCTGGCGTGGATGGGCCCCCTGCCTCTGT 
               
               
                   
               
               
                 GGTTGTGAGGACTGCCCCTGAGCCTGTGGGTCGTGTGTCGAGGCTGCAGA 
               
               
                   
               
               
                 TCCTCAATGCTTCCAGCGACGTTCTACGGATCACCTGGGTAGGGGTCACT 
               
               
                   
               
               
                 GGAGCCACAGCTTACAGACTGGCCTGGGGCCGGAGTGAAGGCGGCCCCAT 
               
               
                   
               
               
                 GAGGCACCAGATACTCCCAGGAAACACAGACTCTGCAGAGATCCGGGGTC 
               
               
                   
               
               
                 TCGAAGGTGGAGTCAGCTACTCAGTGCGAGTGACTGCACTTGTCGGGGAC 
               
               
                   
               
               
                 CGCGAGGGCACACCTGTCTCCATTGTTGTCACTACGCCGCCTGAGGCTCC 
               
               
                   
               
               
                 GCCAGCCCTGGGGACGCTTCACGTGGTGCAGCGCGGGGAGCACTCGCTGA 
               
               
                   
               
               
                 GGCTGCGCTGGGAGCCGGTGCCCAGAGCGCAGGGCTTCCTTCTGCACTGG 
               
               
                   
               
               
                 CAACCTGAGGGTGGCCAGGAACAGTCCCGGGTCCTGGGGCCCGAGCTCAG 
               
               
                   
               
               
                 CAGCTATCACCTGGACGGGCTGGAGCCAGCGACACAGTACCGCGTGAGGC 
               
               
                   
               
               
                 TGAGTGTCCTAGGGCCAGCTGGAGAAGGGCCCTCTGCAGAGGTGACTGCG 
               
               
                   
               
               
                 CGCACTGAGTCACCTCGTGTTCCAAGCATTGAACTACGTGTGGTGGACAC 
               
               
                   
               
               
                 CTCGATCGACTCGGTGACTTTGGCCTGGACTCCAGTGTCCAGGGCATCCA 
               
               
                   
               
               
                 GCTACATCCTATCCTGGCGGCCACTCAGAGGCCCTGGCCAGGAAGTGCCT 
               
               
                   
               
               
                 GGGTCCCCGCAGACACTTCCAGGGATCTCAAGCTCCCAGCGGGTGACAGG 
               
               
                   
               
               
                 GCTAGAGCCTGGCGTCTCTTACATCTTCTCCCTGACGCCTGTCCTGGATG 
               
               
                   
               
               
                 GTGTGCGGGGTCCTGAGGCATCTGTCACACAGACGCCAGTGTGCCCCCGT 
               
               
                   
               
               
                 GGCCTGGCGGATGTGGTGTTCCTACCACATGCCACTCAAGACAATGCTCA 
               
               
                   
               
               
                 CCGTGCGGAGGCTACGAGGAGGGTCCTGGAGCGTCTGGTGTTGGCACTTG 
               
               
                   
               
               
                 GGCCTCTTGGGCCACAGGCAGTTCAGGTTGGCCTGCTGTCTTACAGTCAT 
               
               
                   
               
               
                 CGGCCCTCCCCACTGTTCCCACTGAATGGCTCCCATGACCTTGGCATTAT 
               
               
                   
               
               
                 CTTGCAAAGGATCCGTGACATGCCCTACATGGACCCAAGTGGGAACAACC 
               
               
                   
               
               
                 TGGGCACAGCCGTGGTCACAGCTCACAGATACATGTTGGCACCAGATGCT 
               
               
                   
               
               
                 CCTGGGCGCCGCCAGCACGTACCAGGGGTGATGGTTCTGCTAGTGGATGA 
               
               
                   
               
               
                 ACCCTTGAGAGGTGACATATTCAGCCCCATCCGTGAGGCCCAGGCTTCTG 
               
               
                   
               
               
                 GGCTTAATGTGGTGATGTTGGGAATGGCTGGAGCGGACCCAGAGCAGCTG 
               
               
                   
               
               
                 CGTCGCTTGGCGCCGGGTATGGACTCTGTCCAGACCTTCTTCGCCGTGGA 
               
               
                   
               
               
                 TGATGGGCCAAGCCTGGACCAGGCAGTCAGTGGTCTGGCCACAGCCCTGT 
               
               
                   
               
               
                 GTCAGGCATCCTTCACTACTCAGCCCCGGCCAGAGCCCTGCCCAGTGTAT 
               
               
                   
               
               
                 TGTCCAAAGGGCCAGAAGGGGGAACCTGGAGAGATGGGCCTGAGAGGACA 
               
               
                   
               
               
                 AGTTGGGCCTCCTGGCGACCCTGGCCTCCCGGGCAGGACCGGTGCTCCCG 
               
               
                   
               
               
                 GCCCCCAGGGGCCCCCTGGAAGTGCCACTGCCAAGGGCGAGAGGGGCTTC 
               
               
                   
               
               
                 CCTGGAGCAGATGGGCGTCCAGGCAGCCCTGGCCGCGCCGGGAATCCTGG 
               
               
                   
               
               
                 GACCCCTGGAGCCCCTGGCCTAAAGGGCTCTCCAGGGTTGCCTGGCCCTC 
               
               
                   
               
               
                 GTGGGGACCCGGGAGAGCGAGGACCTCGAGGCCCAAAGGGGGAGCCGGGG 
               
               
                   
               
               
                 GCTCCCGGACAAGTCATCGGAGGTGAAGGACCTGGGCTTCCTGGGCGGAA 
               
               
                   
               
               
                 AGGGGACCCTGGACCATCGGGCCCCCCTGGACCTCGTGGACCACTGGGGG 
               
               
                   
               
               
                 ACCCAGGACCCCGTGGCCCCCCAGGGCTTCCTGGAACAGCCATGAAGGGT 
               
               
                   
               
               
                 GACAAAGGCGATCGTGGGGAGCGGGGTCCCCCTGGACCAGGTGAAGGTGG 
               
               
                   
               
               
                 CATTGCTCCTGGGGAGCCTGGGCTGCCGGGTCTTCCCGGAAGCCCTGGAC 
               
               
                   
               
               
                 CCCAAGGCCCCGTTGGCCCCCCTGGAAAGAAAGGAGAAAAAGGTGACTCT 
               
               
                   
               
               
                 GAGGATGGAGCTCCAGGCCTCCCAGGACAACCTGGGTCTCCGGGTGAGCA 
               
               
                   
               
               
                 GGGCCCACGGGGACCTCCTGGAGCTATTGGCCCCAAAGGTGACCGGGGCT 
               
               
                   
               
               
                 TTCCAGGGCCCCTGGGTGAGGCTGGAGAGAAGGGCGAACGTGGACCCCCA 
               
               
                   
               
               
                 GGCCCAGCGGGATCCCGGGGGCTGCCAGGGGTTGCTGGACGTCCTGGAGC 
               
               
                   
               
               
                 CAAGGGTCCTGAAGGGCCACCAGGACCCACTGGCCGCCAAGGAGAGAAGG 
               
               
                   
               
               
                 GGGAGCCTGGTCGCCCTGGGGACCCTGCAGTGGTGGGACCTGCTGTTGCT 
               
               
                   
               
               
                 GGACCCAAAGGAGAAAAGGGAGATGTGGGGCCCGCTGGGCCCAGAGGAGC 
               
               
                   
               
               
                 TACCGGAGTCCAAGGGGAACGGGGCCCACCCGGCTTGGTTCTTCCTGGAG 
               
               
                   
               
               
                 ACCCTGGCCCCAAGGGAGACCCTGGAGACCGGGGTCCCATTGGCCTTACT 
               
               
                   
               
               
                 GGCAGAGCAGGACCCCCAGGTGACTCAGGGCCTCCTGGAGAGAAGGGAGA 
               
               
                   
               
               
                 CCCTGGGCGGCCTGGCCCCCCAGGACCTGTTGGCCCCCGAGGACGAGATG 
               
               
                   
               
               
                 GTGAAGTTGGAGAGAAAGGTGACGAGGGTCCTCCGGGTGACCCGGGTTTG 
               
               
                   
               
               
                 CCTGGAAAAGCAGGCGAGCGTGGCCTTCGGGGGGCACCTGGAGTTCGGGG 
               
               
                   
               
               
                 GCCTGTGGGTGAAAAGGGAGACCAGGGAGATCCTGGAGAGGATGGACGAA 
               
               
                   
               
               
                 ATGGCAGCCCTGGATCATCTGGACCCAAGGGTGACCGTGGGGAGCCGGGT 
               
               
                   
               
               
                 CCCCCAGGACCCCCGGGACGGCTGGTAGACACAGGACCTGGAGCCAGAGA 
               
               
                   
               
               
                 GAAGGGAGAGCCTGGGGACCGCGGACAAGAGGGTCCTCGAGGGCCCAAGG 
               
               
                   
               
               
                 GTGATCCTGGCCTCCCTGGAGCCCCTGGGGAAAGGGGCATTGAAGGGTTT 
               
               
                   
               
               
                 CGGGGACCCCCAGGCCCACAGGGGGACCCAGGTGTCCGAGGCCCAGCAGG 
               
               
                   
               
               
                 AGAAAAGGGTGACCGGGGTCCCCCTGGGCTGGATGGCCGGAGCGGACTGG 
               
               
                   
               
               
                 ATGGGAAACCAGGAGCCGCTGGGCCCTCTGGGCCGAATGGTGCTGCAGGC 
               
               
                   
               
               
                 AAAGCTGGGGACCCAGGGAGAGACGGGCTTCCAGGCCTCCGTGGAGAACA 
               
               
                   
               
               
                 GGGCCTCCCTGGCCCCTCTGGTCCCCCTGGATTACCGGGAAAGCCAGGCG 
               
               
                   
               
               
                 AGGATGGCAAACCTGGCCTGAATGGAAAAAACGGAGAACCTGGGGACCCT 
               
               
                   
               
               
                 GGAGAAGACGGGAGGAAGGGAGAGAAAGGAGATTCAGGCGCCTCTGGGAG 
               
               
                   
               
               
                 AGAAGGTCGTGATGGCCCCAAGGGTGAGCGTGGAGCTCCTGGTATCCTTG 
               
               
                   
               
               
                 GACCCCAGGGGCCTCCAGGCCTCCCAGGGCCAGTGGGCCCTCCTGGCCAG 
               
               
                   
               
               
                 GGTTTTCCTGGTGTCCCAGGAGGCACGGGCCCCAAGGGTGACCGTGGGGA 
               
               
                   
               
               
                 GACTGGATCCAAAGGGGAGCAGGGCCTCCCTGGAGAGCGTGGCCTGCGAG 
               
               
                   
               
               
                 GAGAGCCTGGAAGTGTGCCGAATGTGGATCGGTTGCTGGAAACTGCTGGC 
               
               
                   
               
               
                 ATCAAGGCATCTGCCCTGCGGGAGATCGTGGAGACCTGGGATGAGAGCTC 
               
               
                   
               
               
                 TGGTAGCTTCCTGCCTGTGCCCGAACGGCGTCGAGGCCCCAAGGGGGACT 
               
               
                   
               
               
                 CAGGCGAACAGGGCCCCCCAGGCAAGGAGGGCCCCATCGGCTTTCCTGGA 
               
               
                   
               
               
                 GAACGCGGGCTGAAGGGCGACCGTGGAGACCCTGGCCCTCAGGGGCCACC 
               
               
                   
               
               
                 TGGTCTGGCCCTTGGGGAGAGGGGCCCCCCCGGGCCTTCCGGCCTTGCCG 
               
               
                   
               
               
                 GGGAGCCTGGAAAGCCTGGTATTCCCGGGCTCCCAGGCAGGGCTGGGGGT 
               
               
                   
               
               
                 GTGGGAGAGGCAGGAAGGCCAGGAGAGAGGGGAGAACGGGGAGAGAAAGG 
               
               
                   
               
               
                 AGAACGTGGAGAACAGGGCAGAGATGGCCCTCCTGGACTCCCTGGAACCC 
               
               
                   
               
               
                 CTGGGCCCCCCGGACCCCCTGGCCCCAAGGTGTCTGTGGATGAGCCAGGT 
               
               
                   
               
               
                 CCTGGACTCTCTGGAGAACAGGGACCCCCTGGACTCAAGGGTGCTAAGGG 
               
               
                   
               
               
                 GGAGCCGGGCAGCAATGGTGACCAAGGTCCCAAAGGAGACAGGGGTGTGC 
               
               
                   
               
               
                 CAGGCATCAAAGGAGACCGGGGAGAGCCTGGACCGAGGGGTCAGGACGGC 
               
               
                   
               
               
                 AACCCGGGTCTACCAGGAGAGCGTGGTATGGCTGGGCCTGAAGGGAAGCC 
               
               
                   
               
               
                 GGGTCTGCAGGGTCCAAGAGGCCCCCCTGGCCCAGTGGGTGGTCATGGAG 
               
               
                   
               
               
                 ACCCTGGACCACCTGGTGCCCCGGGTCTTGCTGGCCCTGCAGGACCCCAA 
               
               
                   
               
               
                 GGACCTTCTGGCCTGAAGGGGGAGCCTGGAGAGACAGGACCTCCAGGACG 
               
               
                   
               
               
                 GGGCCTGACTGGACCTACTGGAGCTGTGGGACTTCCTGGACCCCCCGGCC 
               
               
                   
               
               
                 CTTCAGGCCTTGTGGGTCCACAGGGGTCTCCAGGTTTGCCTGGACAAGTG 
               
               
                   
               
               
                 GGGGAGACAGGGAAGCCGGGAGCCCCAGGTCGAGATGGTGCCAGTGGAAA 
               
               
                   
               
               
                 AGATGGAGACAGAGGGAGCCCTGGTGTGCCAGGGTCACCAGGTCTGCCTG 
               
               
                   
               
               
                 GCCCTGTCGGACCTAAAGGAGAACCTGGCCCCACGGGGGCCCCTGGACAG 
               
               
                   
               
               
                 GCTGTGGTCGGGCTCCCTGGAGCAAAGGGAGAGAAGGGAGCCCCTGGAGG 
               
               
                   
               
               
                 CCTTGCTGGAGACCTGGTGGGTGAGCCGGGAGCCAAAGGTGACCGAGGAC 
               
               
                   
               
               
                 TGCCAGGGCCGCGAGGCGAGAAGGGTGAAGCTGGCCGTGCAGGGGAGCCC 
               
               
                   
               
               
                 GGAGACCCTGGGGAAGATGGTCAGAAAGGGGCTCCAGGACCCAAAGGTTT 
               
               
                   
               
               
                 CAAGGGTGACCCAGGAGTCGGGGTCCCGGGCTCCCCTGGGCCTCCTGGCC 
               
               
                   
               
               
                 CTCCAGGTGTGAAGGGAGATCTGGGCCTCCCTGGCCTGCCCGGTGCTCCT 
               
               
                   
               
               
                 GGTGTTGTTGGGTTCCCGGGTCAGACAGGCCCTCGAGGAGAGATGGGTCA 
               
               
                   
               
               
                 GCCAGGCCCTAGTGGAGAGCGGGGTCTGGCAGGCCCCCCAGGGAGAGAAG 
               
               
                   
               
               
                 GAATCCCAGGACCCCTGGGGCCACCTGGACCACCGGGGTCAGTGGGACCA 
               
               
                   
               
               
                 CCTGGGGCCTCTGGACTCAAAGGAGACAAGGGAGACCCTGGAGTAGGGCT 
               
               
                   
               
               
                 GCCTGGGCCCCGAGGCGAGCGTGGGGAGCCAGGCATCCGGGGTGAAGATG 
               
               
                   
               
               
                 GCCGCCCCGGCCAGGAGGGACCCCGAGGACTCACGGGGCCCCCTGGCAGC 
               
               
                   
               
               
                 AGGGGAGAGCGTGGGGAGAAGGGTGATGTTGGGAGTGCAGGACTAAAGGG 
               
               
                   
               
               
                 TGACAAGGGAGACTCAGCTGTGATCCTGGGGCCTCCAGGCCCACGGGGTG 
               
               
                   
               
               
                 CCAAGGGGGACATGGGTGAACGAGGGCCTCGGGGCTTGGATGGTGACAAA 
               
               
                   
               
               
                 GGACCTCGGGGAGACAATGGGGACCCTGGTGACAAGGGCAGCAAGGGAGA 
               
               
                   
               
               
                 GCCTGGTGACAAGGGCTCAGCCGGGTTGCCAGGACTGCGTGGACTCCTGG 
               
               
                   
               
               
                 GACCCCAGGGTCAACCTGGTGCAGCAGGGATCCCTGGTGACCCGGGATCC 
               
               
                   
               
               
                 CCAGGAAAGGATGGAGTGCCTGGTATCCGAGGAGAAAAAGGAGATGTTGG 
               
               
                   
               
               
                 CTTCATGGGTCCCCGGGGCCTCAAGGGTGAACGGGGAGTGAAGGGAGCCT 
               
               
                   
               
               
                 GTGGCCTTGATGGAGAGAAGGGAGACAAGGGAGAAGCTGGTCCCCCAGGC 
               
               
                   
               
               
                 CGCCCCGGGCTGGCAGGACACAAAGGAGAGATGGGGGAGCCTGGTGTGCC 
               
               
                   
               
               
                 GGGCCAGTCGGGGGCCCCTGGCAAGGAGGGCCTGATCGGTCCCAAGGGTG 
               
               
                   
               
               
                 ACCGAGGCTTTGACGGGCAGCCAGGCCCCAAGGGTGACCAGGGCGAGAAA 
               
               
                   
               
               
                 GGGGAGCGGGGAACCCCAGGAATTGGGGGCTTCCCAGGCCCCAGTGGAAA 
               
               
                   
               
               
                 TGATGGCTCTGCTGGTCCCCCAGGGCCACCTGGCAGTGTTGGTCCCAGAG 
               
               
                   
               
               
                 GCCCCGAAGGACTTCAGGGCCAGAAGGGTGAGCGAGGTCCCCCCGGAGAG 
               
               
                   
               
               
                 AGAGTGGTGGGGGCTCCTGGGGTCCCTGGAGCTCCTGGCGAGAGAGGGGA 
               
               
                   
               
               
                 GCAGGGGCGGCCAGGGCCTGCCGGTCCTCGAGGCGAGAAGGGAGAAGCTG 
               
               
                   
               
               
                 CACTGACGGAGGATGACATCCGGGGCTTTGTGCGCCAAGAGATGAGTCAG 
               
               
                   
               
               
                 CACTGTGCCTGCCAGGGCCAGTTCATCGCATCTGGATCACGACCCCTCCC 
               
               
                   
               
               
                 TAGTTATGCTGCAGACACTGCCGGCTCCCAGCTCCATGCTGTGCCTGTGC 
               
               
                   
               
               
                 TCCGCGTCTCTCATGCAGAGGAGGAAGAGCGGGTACCCCCTGAGGATGAT 
               
               
                   
               
               
                 GAGTACTCTGAATACTCCGAGTATTCTGTGGAGGAGTACCAGGACCCTGA 
               
               
                   
               
               
                 AGCTCCTTGGGATAGTGATGACCCCTGTTCCCTGCCACTGGATGAGGGCT 
               
               
                   
               
               
                 CCTGCACTGCCTACACCCTGCGCTGGTACCATCGGGCTGTGACAGGCAGC 
               
               
                   
               
               
                 ACAGAGGCCTGTCACCCTTTTGTCTATGGTGGCTGTGGAGGGAATGCCAA 
               
               
                   
               
               
                 CCGTTTTGGGACCCGTGAGGCCTGCGAGCGCCGCTGCCCACCCCGGGTGG 
               
               
                   
               
               
                 TCCAGAGCCAGGGGACAGGTACTGCCCAGGACTGA 
               
            
           
         
       
     
     The protein sequence is: 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 2) 
                   
               
               
                 MTLRLLVAALCAGILAEAPRVRAQHRERVTCTRLYAADIVFLLDGSSSIGRSNFREVRSF 
                   
               
               
                   
               
               
                 LEGLVLPFSGAASAQGVRFATVQYSDDPRTEFGLDALGSGGDVIRAIRELSYKGGNTRTG 
               
               
                   
               
               
                 AAILHVADHVFLPQLARPGVPKVCILITDGKSQDLVDTAAQRLKGQGVKLFAVGIKNADP 
               
               
                   
               
               
                 EELKRVASQPTSDFFFFVNDFSILRTLLPLVSRRVCTTAGGVPVTRPPDDSTSAPRDLVL 
               
               
                   
               
               
                 SEPSSQSLRVQWTAASGPVTGYKVQYTPLTGLGQPLPSERQEVNVPAGETSVRLRGLRPL 
               
               
                   
               
               
                 TEYQVTVIALYANSIGEAVSGTARTTALEGPELTIQNTTAHSLLVAWRSVPGATGYRVTW 
               
               
                   
               
               
                 RVLSGGPTQQQELGPGQGSVLLRDLEPGTDYEVTVSTLFGRSVGPATSLMARTDASVEQT 
               
               
                   
               
               
                 LRPVILGPTSILLSWNLVPEARGYRLEWRRETGLEPPQKVVLPSDVTRYQLDGLQPGTEY 
               
               
                   
               
               
                 RLTLYTLLEGHEVATPATVVPTGPELPVSPVTDLQATELPGQRVRVSWSPVPGATQYRII 
               
               
                   
               
               
                 VRSTQGVERTLVLPGSQTAFDLDDVQAGLSYTVRVSARVGPREGSASVLTVRREPETPLA 
               
               
                   
               
               
                 VPGLRVVVSDATRVRVAWGPVPGASGFRISWSTGSGPESSQTLPPDSTATDITGLQPGTT 
               
               
                   
               
               
                 YQVAVSVLRGREEGPAAVIVARTDPLGPVRTVHVTQASSSSVTITWTRVPGATGYRVSWH 
               
               
                   
               
               
                 SAHGPEKSQLVSGEATVAELDGLEPDTEYTVHVRAHVAGVDGPPASVVVRTAPEPVGRVS 
               
               
                   
               
               
                 RLQILNASSDVLRITWVGVTGATAYRLAWGRSEGGPMRHQILPGNTDSAEIRGLEGGVSY 
               
               
                   
               
               
                 SVRVTALVGDREGTPVSIVVTTPPEAPPALGTLHVVQRGEHSLRLRWEPVPRAQGFLLHW 
               
               
                   
               
               
                 QPEGGQEQSRVLGPELSSYHLDGLEPATQYRVRLSVLGPAGEGPSAEVTARTESPRVPSI 
               
               
                   
               
               
                 ELRVVDTSIDSVTLAWTPVSRASSYILSWRPLRGPGQEVPGSPQTLPGISSSQRVTGLEP 
               
               
                   
               
               
                 GVSYIFSLTPVLDGVRGPEASVTQTPVCPRGLADVVFLPHATQDNAHRAEATRRVLERLV 
               
               
                   
               
               
                 LALGPLGPQAVQVGLLSYSHRPSPLFPLNGSHDLGIILQRIRDMPYMDPSGNNLGTAVVT 
               
               
                   
               
               
                 AHRYMLAPDAPGRRQHVPGVMVLLVDEPLRGDIFSPIREAQASGLNVVMLGMAGADPEQL 
               
               
                   
               
               
                 RRLAPGMDSVQTFFAVDDGPSLDQAVSGLATALCQASFTTQPRPEPCPVYCPKGQKGEPG 
               
               
                   
               
               
                 EMGLRGQVGPPGDPGLPGRTGAPGPQGPPGSATAKGERGFPGADGRPGSPGRAGNPGTPG 
               
               
                   
               
               
                 APGLKGSPGLPGPRGDPGERGPRGPKGEPGAPGQVIGGEGPGLPGRKGDPGPSGPPGPRG 
               
               
                   
               
               
                 PLGDPGPRGPPGLPGTAMKGDKGDRGERGPPGPGEGGIAPGEPGLPGLPGSPGPQGPVGP 
               
               
                   
               
               
                 PGKKGEKGDSEDGAPGLPGQPGSPGEQGPRGPPGAIGPKGDRGFPGPLGEAGEKGERGPP 
               
               
                   
               
               
                 GPAGSRGLPGVAGRPGAKGPEGPPGPTGRQGEKGEPGRPGDPAVVGPAVAGPKGEKGDVG 
               
               
                   
               
               
                 PAGPRGATGVQGERGPPGLVLPGDPGPKGDPGDRGPIGLTGRAGPPGDSGPPGEKGDPGR 
               
               
                   
               
               
                 PGPPGPVGPRGRDGEVGEKGDEGPPGDPGLPGKAGERGLRGAPGVRGPVGEKGDQGDPGE 
               
               
                   
               
               
                 DGRNGSPGSSGPKGDRGEPGPPGPPGRLVDTGPGAREKGEPGDRGQEGPRGPKGDPGLPG 
               
               
                   
               
               
                 APGERGIEGFRGPPGPQGDPGVRGPAGEKGDRGPPGLDGRSGLDGKPGAAGPSGPNGAAG 
               
               
                   
               
               
                 KAGDPGRDGLPGLRGEQGLPGPSGPPGLPGKPGEDGKPGLNGKNGEPGDPGEDGRKGEKG 
               
               
                   
               
               
                 DSGASGREGRDGPKGERGAPGILGPQGPPGLPGPVGPPGQGFPGVPGGTGPKGDRGETGS 
               
               
                   
               
               
                 KGEQGLPGERGLRGEPGSVPNVDRLLETAGIKASALREIVETWDESSGSFLPVPERRRGP 
               
               
                   
               
               
                 KGDSGEQGPPGKEGPIGFPGERGLKGDRGDPGPQGPPGLALGERGPPGPSGLAGEPGKPG 
               
               
                   
               
               
                 IPGLPGRAGGVGEAGRPGERGERGEKGERGEQGRDGPPGLPGTPGPPGPPGPKVSVDEPG 
               
               
                   
               
               
                 PGLSGEQGPPGLKGAKGEPGSNGDQGPKGDRGVPGIKGDRGEPGPRGQDGNPGLPGERGM 
               
               
                   
               
               
                 AGPEGKPGLQGPRGPPGPVGGHGDPGPPGAPGLAGPAGPQGPSGLKGEPGETGPPGRGLT 
               
               
                   
               
               
                 GPTGAVGLPGPPGPSGLVGPQGSPGLPGQVGETGKPGAPGRDGASGKDGDRGSPGVPGSP 
               
               
                   
               
               
                 GLPGPVGPKGEPGPTGAPGQAVVGLPGAKGEKGAPGGLAGDLVGEPGAKGDRGLPGPRGE 
               
               
                   
               
               
                 KGEAGRAGEPGDPGEDGQKGAPGPKGFKGDPGVGVPGSPGPPGPPGVKGDLGLPGLPGAP 
               
               
                   
               
               
                 GVVGFPGQTGPRGEMGQPGPSGERGLAGPPGREGIPGPLGPPGPPGSVGPPGASGLKGDK 
               
               
                   
               
               
                 GDPGVGLPGPRGERGEPGIRGEDGRPGQEGPRGLTGPPGSRGERGEKGDVGSAGLKGDKG 
               
               
                   
               
               
                 DSAVILGPPGPRGAKGDMGERGPRGLDGDKGPRGDNGDPGDKGSKGEPGDKGSAGLPGLR 
               
               
                   
               
               
                 GLLGPQGQPGAAGIPGDPGSPGKDGVPGIRGEKGDVGFMGPRGLKGERGVKGACGLDGEK 
               
               
                   
               
               
                 GDKGEAGPPGRPGLAGHKGEMGEPGVPGQSGAPGKEGLIGPKGDRGFDGQPGPKGDQGEK 
               
               
                   
               
               
                 GERGTPGIGGFPGPSGNDGSAGPPGPPGSVGPRGPEGLQGQKGERGPPGERVVGAPGVPG 
               
               
                   
               
               
                 APGERGEQGRPGPAGPRGEKGEAALTEDDIRGEVRQEMSQHCACQGQFIASGSRPLPSYA 
               
               
                   
               
               
                 ADTAGSQLHAVPVLRVSHAEEEERVPPEDDEYSEYSEYSVEEYQDPEAPWDSDDPCSLPL 
               
               
                   
               
               
                 DEGSCTAYTLRWYHRAVTGSTEACHPFVYGGCGGNANRFGTREACERRCPPRVVQSQGTG 
               
               
                   
               
               
                 TAQD 
               
            
           
         
       
     
     Preferably, collagen 17 is characterized by the sequence disclosed in the NCBI Data Bank with the Accession no.: NM_000494.3 (COL17A1). The cDNA sequence is: 
     
       
         
           
               
            
               
                 (SEQ ID NO: 3) 
               
               
                 ATGGATGTAACCAAGAAAAACAAACGAGATGGAACTGAAGTCACTGAGAG 
               
               
                   
               
               
                 AATTGTCACTGAAACAGTAACCACAAGACTTACATCCTTACCACCAAAAG 
               
               
                   
               
               
                 GCGGGACCAGCAATGGCTATGCTAAAACAGCCTCTCTTGGTGGAGGGAGC 
               
               
                   
               
               
                 CGGCTGGAGAAACAAAGCCTGACTCATGGCAGCAGCGGCTACATAAACTC 
               
               
                   
               
               
                 AACTGGAAGCACACGAGGCCATGCCTCCACCTCTAGTTACAGGAGGGCTC 
               
               
                   
               
               
                 ACTCACCTGCCTCCACTCTGCCCAACTCCCCAGGCTCAACCTTTGAAAGG 
               
               
                   
               
               
                 AAAACTCACGTTACCCGCCATGCGTATGAAGGGAGCTCCAGTGGCAACTC 
               
               
                   
               
               
                 TTCTCCGGAGTACCCTCGGAAGGAATTTGCATCTTCTTCAACCAGAGGAC 
               
               
                   
               
               
                 GGAGTCAAACACGAGAGAGTGAAATTCGAGTTCGACTGCAGAGTGCGTCC 
               
               
                   
               
               
                 CCATCCACCCGATGGACAGAATTGGATGATGTTAAGCGTTTGCTCAAGGG 
               
               
                   
               
               
                 GAGTCGATCGGCAAGTGTGAGCCCCACCCGGAATTCCTCCAACACACTCC 
               
               
                   
               
               
                 CCATCCCCAAGAAAGGCACTGTGGAGACCAAAATTGTGACAGCGAGCTCC 
               
               
                   
               
               
                 CAGTCGGTGTCAGGCACCTACGATGCAACGATCCTGGATGCCAACCTTCC 
               
               
                   
               
               
                 CTCCCATGTGTGGTCCTCCACCCTGCCCGCGGGGTCCTCCATGGGGACCT 
               
               
                   
               
               
                 ATCACAACAACATGACAACCCAGAGCTCATCCCTCCTCAACACCAATGCC 
               
               
                   
               
               
                 TACTCTGCGGGATCAGTCTTCGGAGTTCCAAACAACATGGCGTCCTGCTC 
               
               
                   
               
               
                 ACCCACTTTGCACCCTGGACTCAGCACATCCTCCTCAGTGTTTGGCATGC 
               
               
                   
               
               
                 AGAACAATCTGGCCCCCAGCTTGACCACCCTGTCCCATGGCACCACCACC 
               
               
                   
               
               
                 ACTTCCACAGCATATGGGGTGAAGAAAAACATGCCCCAGAGTCCTGCGGC 
               
               
                   
               
               
                 TGTGAACACTGGCGTTTCCACCTCCGCCGCCTGCACCACAAGTGTGCAGA 
               
               
                   
               
               
                 GCGATGACCTTTTGCACAAGGACTGCAAGTTCCTGATCCTAGAGAAAGAC 
               
               
                   
               
               
                 AACACACCTGCCAAGAAGGAGATGGAGCTGCTCATCATGACCAAGGACAG 
               
               
                   
               
               
                 CGGGAAGGTCTTTACAGCCTCCCCTGCCAGCATCGCTGCAACTTCTTTTT 
               
               
                   
               
               
                 CAGAAGACACCCTAAAAAAAGAAAAGCAAGCTGCCTACAATGCTGACTCA 
               
               
                   
               
               
                 GGCCTAAAAGCCGAAGCTAATGGAGACCTGAAGACTGTGTCCACAAAGGG 
               
               
                   
               
               
                 CAAGACCACCACTGCAGATATCCACAGCTACGGCAGCAGTGGTGGTGGTG 
               
               
                   
               
               
                 GCAGTGGAGGAGGTGGCGGTGTTGGTGGCGCTGGCGGCGGCCCTTGGGGA 
               
               
                   
               
               
                 CCAGCGCCAGCCTGGTGCCCCTGCGGCTCCTGCTGCAGCTGGTGGAAGTG 
               
               
                   
               
               
                 GCTGCTGGGCCTGCTGCTCACCTGGCTGCTACTCCTGGGGCTGCTCTTCG 
               
               
                   
               
               
                 GCCTCATTGCTCTGGCGGAGGAGGTGAGGAAGCTGAAGGCGCGTGTGGAT 
               
               
                   
               
               
                 GAGCTGGAGAGGATCAGGAGGAGCATACTGCCCTATGGGGACAGCATGGA 
               
               
                   
               
               
                 TAGAATAGAAAAGGACCGCCTCCAGGGCATGGCACCCGCGGCGGGAGCAG 
               
               
                   
               
               
                 ACCTGGACAAAATTGGGCTGCACAGTGACAGCCAGGAGGAGCTCTGGATG 
               
               
                   
               
               
                 TTCGTGAGGAAGAAGCTAATGATGGAACAGGAAAATGGAAATCTCCGAGG 
               
               
                   
               
               
                 AAGCCCTGGCCCTAAAGGTGACATGGGAAGTCCAGGCCCTAAAGGAGATC 
               
               
                   
               
               
                 GAGGGTTCCCTGGGACTCCAGGTATCCCTGGGCCCTTGGGCCACCCAGGT 
               
               
                   
               
               
                 CCACAAGGACCAAAGGGTCAAAAAGGCAGCGTGGGAGATCCTGGCATGGA 
               
               
                   
               
               
                 AGGCCCCATGGGCCAGAGAGGGCGAGAAGGCCCCATGGGACCTCGTGGTG 
               
               
                   
               
               
                 AGGCAGGGCCTCCTGGATCTGGAGAGAAAGGGGAAAGAGGGGCTGCTGGT 
               
               
                   
               
               
                 GAACCAGGTCCTCATGGCCCACCTGGTGTCCCAGGTTCTGTGGGTCCCAA 
               
               
                   
               
               
                 AGGTTCCAGCGGCTCTCCTGGCCCACAGGGCCCTCCAGGTCCTGTAGGTC 
               
               
                   
               
               
                 TCCAAGGGCTCCGAGGTGAAGTAGGACTTCCTGGTGTCAAAGGTGACAAA 
               
               
                   
               
               
                 GGACCAATGGGACCACCAGGACCCAAAGGTGACCAGGGTGAGAAAGGACC 
               
               
                   
               
               
                 TCGAGGCCTCACAGGCGAGCCTGGCATGAGAGGTTTGCCTGGTGCTGTTG 
               
               
                   
               
               
                 GTGAGCCCGGGGCTAAAGGAGCAATGGGTCCTGCTGGCCCAGACGGACAC 
               
               
                   
               
               
                 CAAGGCCCAAGAGGTGAACAAGGTCTTACTGGGATGCCTGGAATCCGTGG 
               
               
                   
               
               
                 CCCACCAGGACCTTCTGGAGACCCAGGAAAGCCAGGTCTCACAGGACCCC 
               
               
                   
               
               
                 AGGGACCTCAGGGACTTCCCGGTACCCCTGGCCGACCAGGAATAAAAGGT 
               
               
                   
               
               
                 GAACCAGGAGCTCCAGGCAAGATCGTGACTTCGGAGGGGTCATCGATGCT 
               
               
                   
               
               
                 CACTGTCCCAGGCCCCCCAGGACCTCCTGGAGCCATGGGACCCCCAGGAC 
               
               
                   
               
               
                 CTCCAGGTGCCCCAGGCCCTGCCGGCCCAGCTGGTCTCCCAGGACATCAA 
               
               
                   
               
               
                 GAAGTTCTTAATTTACAAGGTCCCCCAGGCCCACCCGGCCCACGCGGGCC 
               
               
                   
               
               
                 ACCAGGGCCTTCCATTCCAGGCCCACCAGGACCCCGAGGCCCACCAGGGG 
               
               
                   
               
               
                 AGGGTTTGCCAGGCCCACCAGGCCCACCAGGATCGTTCCTGTCCAACTCA 
               
               
                   
               
               
                 GAAACCTTCCTCTCCGGCCCCCCAGGCCCACCTGGCCCCCCAGGTCCCAA 
               
               
                   
               
               
                 GGGAGACCAAGGTCCCCCAGGCCCCAGAGGACACCAAGGCGAGCAAGGCC 
               
               
                   
               
               
                 TCCCAGGTTTCTCAACCTCAGGGTCCAGTTCTTTCGGACTCAACCTTCAG 
               
               
                   
               
               
                 GGACCACCAGGCCCACCTGGCCCCCAGGGACCCAAAGGTGACAAAGGTGA 
               
               
                   
               
               
                 TCCAGGTGTTCCAGGGGCTCTTGGCATTCCTAGTGGTCCTTCTGAAGGGG 
               
               
                   
               
               
                 GATCATCAAGTACCATGTACGTGTCAGGCCCGCCAGGGCCCCCTGGGCCC 
               
               
                   
               
               
                 CCTGGGCCTCCGGGCTCTATCAGCAGCTCTGGCCAGGAGATTCAGCAGTA 
               
               
                   
               
               
                 CATCTCTGAGTACATGCAGAGTGACAGTATTAGATCTTACCTATCCGGAG 
               
               
                   
               
               
                 TTCAGGGTCCCCCAGGCCCACCTGGTCCCCCAGGACCTGTCACCACCATC 
               
               
                   
               
               
                 ACAGGCGAGACTTTCGACTACTCAGAGCTGGCAAGCCACGTTGTGAGCTA 
               
               
                   
               
               
                 CTTACGGACTTCGGGGTACGGTGTCAGCTTGTTCTCGTCCTCCATCTCTT 
               
               
                   
               
               
                 CTGAAGACATTCTGGCTGTGCTGCAGCGGGATGACGTGCGTCAGTACCTA 
               
               
                   
               
               
                 CGTCAGTACTTGATGGGCCCTCGGGGTCCGCCAGGGCCACCAGGAGCCAG 
               
               
                   
               
               
                 TGGAGATGGGTCCCTCCTGTCTTTGGACTATGCAGAGCTGAGTAGTCGCA 
               
               
                   
               
               
                 TTCTCAGCTACATGTCGAGTTCTGGGATCAGCATTGGGCTTCCTGGTCCC 
               
               
                   
               
               
                 CCGGGGCCCCCTGGCTTGCCGGGAACCTCCTATGAGGAGCTCCTCTCCTT 
               
               
                   
               
               
                 GCTGCGAGGGTCTGAATTCAGAGGCATCGTTGGACCCCCAGGTCCCCCGG 
               
               
                   
               
               
                 GTCCACCAGGGATCCCAGGCAATGTGTGGTCCAGCATCAGCGTGGAGGAC 
               
               
                   
               
               
                 CTCTCGTCTTACTTACATACTGCCGGCTTGTCATTCATCCCAGGCCCTCC 
               
               
                   
               
               
                 AGGACCTCCTGGTCCCCCAGGGCCTCGAGGGCCCCCGGGTGTCTCAGGAG 
               
               
                   
               
               
                 CCCTGGCAACCTATGCAGCTGAAAACAGCGACAGCTTCCGGAGCGAGCTG 
               
               
                   
               
               
                 ATCAGCTACCTCACAAGTCCTGATGTGCGCAGCTTCATTGTTGGCCCCCC 
               
               
                   
               
               
                 AGGCCCTCCTGGGCCGCAGGGACCCCCTGGGGACAGCCGCCTCCTGTCCA 
               
               
                   
               
               
                 CGGATGCCTCCCACAGTCGGGGTAGCAGCTCCTCCTCACACAGCTCATCT 
               
               
                   
               
               
                 GTCAGGCGGGGCAGCTCCTACAGCTCTTCCATGAGCACAGGAGGAGGTGG 
               
               
                   
               
               
                 TGCAGGCTCCCTGGGTGCAGGCGGTGCCTTTGGTGAAGCTGCAGGAGACA 
               
               
                   
               
               
                 GGGGTCCCTATGGCACTGACATCGGCCCAGGCGGAGGCTATGGGGCAGCA 
               
               
                   
               
               
                 GCAGAAGGCGGCATGTATGCTGGCAATGGCGGACTATTGGGAGCTGACTT 
               
               
                   
               
               
                 TGCTGGAGATCTGGATTACAATGAGCTGGCTGTGAGGGTGTCAGAGAGCA 
               
               
                   
               
               
                 TGCAGCGTCAGGGCCTACTGCAAGGGATGGCCTACACTGTCCAGGGCCCA 
               
               
                   
               
               
                 CCAGGCCAGCCTGGGCCACAGGGGCCACCCGGCATCAGCAAGGTCTTCTC 
               
               
                   
               
               
                 TGCCTACAGCAACGTGACTGCGGACCTCATGGACTTCTTCCAAACTTATG 
               
               
                   
               
               
                 GAGCCATTCAAGGACCCCCTGGGCAAAAAGGAGAGATGGGCACTCCAGGA 
               
               
                   
               
               
                 CCCAAAGGTGACAGGGGCCCTGCTGGGCCACCAGGTCATCCTGGGCCACC 
               
               
                   
               
               
                 TGGCCCTCGAGGACACAAGGGAGAAAAAGGAGACAAAGGTGACCAAGTCT 
               
               
                   
               
               
                 ATGCTGGGCGGAGAAGGAGAAGAAGTATTGCTGTCAAGCCGTGA 
               
            
           
         
       
     
     The protein sequence is: 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 4) 
                   
               
               
                 MDVTKKNKRDGTEVTERIVTETVTTRLTSLPPKGGTSNGYAKTASLGGGSRLEKQSLTHG 
                   
               
               
                   
               
               
                 SSGYINSTGSTRGHASTSSYRRAHSPASTLPNSPGSTFERKTHVTRHAYEGSSSGNSSPE 
               
               
                   
               
               
                 YPRKEFASSSTRGRSQTRESEIRVRLQSASPSTRWTELDDVKRLLKGSRSASVSPTRNSS 
               
               
                   
               
               
                 NTLPIPKKGTVETKIVTASSQSVSGTYDATILDANLPSHVWSSTLPAGSSMGTYHNNMTT 
               
               
                   
               
               
                 QSSSLLNTNAYSAGSVFGVPNNMASCSPTLHPGLSTSSSVFGMQNNLAPSLTTLSHGTTT 
               
               
                   
               
               
                 TSTAYGVKKNMPQSPAAVNTGVSTSAACTTSVQSDDLLHKDCKFLILEKDNTPAKKEMEL 
               
               
                   
               
               
                 LIMTKDSGKVFTASPASIAATSFSEDTLKKEKQAAYNADSGLKAEANGDLKTVSTKGKTT 
               
               
                   
               
               
                 TADIHSYGSSGGGGSGGGGGVGGAGGGPWGPAPAWCPCGSCCSWWKWLLGLLLTWLLLLG 
               
               
                   
               
               
                 LLFGLIALAEEVRKLKARVDELERIRRSILPYGDSMDRIEKDRLQGMAPAAGADLDKIGL 
               
               
                   
               
               
                 HSDSQEELWMFVRKKLMMEQENGNLRGSPGPKGDMGSPGPKGDRGFPGTPGIPGPLGHPG 
               
               
                   
               
               
                 PQGPKGQKGSVGDPGMEGPMGQRGREGPMGPRGEAGPPGSGEKGERGAAGEPGPHGPPGV 
               
               
                   
               
               
                 PGSVGPKGSSGSPGPQGPPGPVGLQGLRGEVGLPGVKGDKGPMGPPGPKGDQGEKGPRGL 
               
               
                   
               
               
                 TGEPGMRGLPGAVGEPGAKGAMGPAGPDGHQGPRGEQGLTGMPGIRGPPGPSGDPGKPGL 
               
               
                   
               
               
                 TGPQGPQGLPGTPGRPGIKGEPGAPGKIVTSEGSSMLTVPGPPGPPGAMGPPGPPGAPGP 
               
               
                   
               
               
                 AGPAGLPGHQEVLNLQGPPGPPGPRGPPGPSIPGPPGPRGPPGEGLPGPPGPPGSFLSNS 
               
               
                   
               
               
                 ETFLSGPPGPPGPPGPKGDQGPPGPRGHQGEQGLPGFSTSGSSSFGLNLQGPPGPPGPQG 
               
               
                   
               
               
                 PKGDKGDPGVPGALGIPSGPSEGGSSSTMYVSGPPGPPGPPGPPGSISSSGQEIQQYISE 
               
               
                   
               
               
                 YMQSDSIRSYLSGVQGPPGPPGPPGPVTTITGETFDYSELASHVVSYLRTSGYGVSLFSS 
               
               
                   
               
               
                 SISSEDILAVLQRDDVRQYLRQYLMGPRGPPGPPGASGDGSLLSLDYAELSSRILSYMSS 
               
               
                   
               
               
                 SGISIGLPGPPGPPGLPGTSYEELLSLLRGSEFRGIVGPPGPPGPPGIPGNVWSSISVED 
               
               
                   
               
               
                 LSSYLHTAGLSFIPGPPGPPGPPGPRGPPGVSGALATYAAENSDSFRSELISYLTSPDVR 
               
               
                   
               
               
                 SFIVGPPGPPGPQGPPGDSRLLSTDASHSRGSSSSSHSSSVRRGSSYSSSMSTGGGGAGS 
               
               
                   
               
               
                 LGAGGAFGEAAGDRGPYGTDIGPGGGYGAAAEGGMYAGNGGLLGADFAGDLDYNELAVRV 
               
               
                   
               
               
                 SESMQRQGLLQGMAYTVQGPPGQPGPQGPPGISKVFSAYSNVTADLMDFFQTYGAIQGPP 
               
               
                   
               
               
                 GQKGEMGTPGPKGDRGPAGPPGHPGPPGPRGHKGEKGDKGDQVYAGRRRRRSIAVKP 
               
            
           
         
       
     
     Preferably, the beta-3 chain of laminin 5 is characterized by the sequence disclosed in the NCBI Data Bank with the Accession no.: NM_000228-Q13751 (LAMB3). The cDNA sequence is: 
     
       
         
           
               
            
               
                 (SEQ ID NO: 5) 
               
               
                 ATGAGACCATTCTTCCTCTTGTGTTTTGCCCTGCCTGGCCTCCTGCATGC 
               
               
                   
               
               
                 CCAACAAGCCTGCTCCCGTGGGGCCTGCTATCCACCTGTTGGGGACCTGC 
               
               
                   
               
               
                 TTGTTGGGAGGACCCGGTTTCTCCGAGCTTCATCTACCTGTGGACTGACC 
               
               
                   
               
               
                 AAGCCTGAGACCTACTGCACCCAGTATGGCGAGTGGCAGATGAAATGCTG 
               
               
                   
               
               
                 CAAGTGTGACTCCAGGCAGCCTCACAACTACTACAGTCACCGAGTAGAGA 
               
               
                   
               
               
                 ATGTGGCTTCATCCTCCGGCCCCATGCGCTGGTGGCAGTCACAGAATGAT 
               
               
                   
               
               
                 GTGAACCCTGTCTCTCTGCAGCTGGACCTGGACAGGAGATTCCAGCTTCA 
               
               
                   
               
               
                 AGAAGTCATGATGGAGTTCCAGGGGCCCATGCCCGCCGGCATGCTGATTG 
               
               
                   
               
               
                 AGCGCTCCTCAGACTTCGGTAAGACCTGGCGAGTGTACCAGTACCTGGCT 
               
               
                   
               
               
                 GCCGACTGCACCTCCACCTTCCCTCGGGTCCGCCAGGGTCGGCCTCAGAG 
               
               
                   
               
               
                 CTGGCAGGATGTTCGGTGCCAGTCCCTGCCTCAGAGGCCTAATGCACGCC 
               
               
                   
               
               
                 TAAATGGGGGGAAGGTCCAACTTAACCTTATGGATTTAGTGTCTGGGATT 
               
               
                   
               
               
                 CCAGCAACTCAAAGTCAAAAAATTCAAGAGGTGGGGGAGATCACAAACTT 
               
               
                   
               
               
                 GAGAGTCAATTTCACCAGGCTGGCCCCTGTGCCCCAAAGGGGCTACCACC 
               
               
                   
               
               
                 CTCCCAGCGCCTACTATGCTGTGTCCCAGCTCCGTCTGCAGGGGAGCTGC 
               
               
                   
               
               
                 TTCTGTCACGGCCATGCTGATCGCTGCGCACCCAAGCCTGGGGCCTCTGC 
               
               
                   
               
               
                 AGGCCCCTCCACCGCTGTGCAGGTCCACGATGTCTGTGTCTGCCAGCACA 
               
               
                   
               
               
                 ACACTGCCGGCCCAAATTGTGAGCGCTGTGCACCCTTCTACAACAACCGG 
               
               
                   
               
               
                 CCCTGGAGACCGGCGGAGGGCCAGGACGCCCATGAATGCCAAAGGTGCGA 
               
               
                   
               
               
                 CTGCAATGGGCACTCAGAGACATGTCACTTTGACCCCGCTGTGTTTGCCG 
               
               
                   
               
               
                 CCAGCCAGGGGGCATATGGAGGTGTGTGTGACAATTGCCGGGACCACACC 
               
               
                   
               
               
                 GAAGGCAAGAACTGTGAGCGGTGTCAGCTGCACTATTTCCGGAACCGGCG 
               
               
                   
               
               
                 CCCGGGAGCTTCCATTCAGGAGACCTGCATCTCCTGCGAGTGTGATCCGG 
               
               
                   
               
               
                 ATGGGGCAGTGCCAGGGGCTCCCTGTGACCCAGTGACCGGGCAGTGTGTG 
               
               
                   
               
               
                 TGCAAGGAGCATGTGCAGGGAGAGCGCTGTGACCTATGCAAGCCGGGCTT 
               
               
                   
               
               
                 CACTGGACTCACCTACGCCAACCCGCAGGGCTGCCACCGCTGTGACTGCA 
               
               
                   
               
               
                 ACATCCTGGGGTCCCGGAGGGACATGCCGTGTGACGAGGAGAGTGGGCGC 
               
               
                   
               
               
                 TGCCTTTGTCTGCCCAACGTGGTGGGTCCCAAATGTGACCAGTGTGCTCC 
               
               
                   
               
               
                 CTACCACTGGAAGCTGGCCAGTGGCCAGGGCTGTGAACCGTGTGCCTGCG 
               
               
                   
               
               
                 ACCCGCACAACTCCCTCAGCCCACAGTGCAACCAGTTCACAGGGCAGTGC 
               
               
                   
               
               
                 CCCTGTCGGGAAGGCTTTGGTGGCCTGATGTGCAGCGCTGCAGCCATCCG 
               
               
                   
               
               
                 CCAGTGTCCAGACCGGACCTATGGAGACGTGGCCACAGGATGCCGAGCCT 
               
               
                   
               
               
                 GTGACTGTGATTTCCGGGGAACAGAGGGCCCGGGCTGCGACAAGGCATCA 
               
               
                   
               
               
                 GGCCGCTGCCTCTGCCGCCCTGGCTTGACCGGGCCCCGCTGTGACCAGTG 
               
               
                   
               
               
                 CCAGCGAGGCTACTGTAATCGCTACCCGGTGTGCGTGGCCTGCCACCCTT 
               
               
                   
               
               
                 GCTTCCAGACCTATGATGCGGACCTCCGGGAGCAGGCCCTGCGCTTTGGT 
               
               
                   
               
               
                 AGACTCCGCAATGCCACCGCCAGCCTGTGGTCAGGGCCTGGGCTGGAGGA 
               
               
                   
               
               
                 CCGTGGCCTGGCCTCCCGGATCCTAGATGCAAAGAGTAAGATTGAGCAGA 
               
               
                   
               
               
                 TCCGAGCAGTTCTCAGCAGCCCCGCAGTCACAGAGCAGGAGGTGGCTCAG 
               
               
                   
               
               
                 GTGGCCAGTGCCATCCTCTCCCTCAGGCGAACTCTCCAGGGCCTGCAGCT 
               
               
                   
               
               
                 GGATCTGCCCCTGGAGGAGGAGACGTTGTCCCTTCCGAGAGACCTGGAGA 
               
               
                   
               
               
                 GTCTTGACAGAAGCTTCAATGGTCTCCTTACTATGTATCAGAGGAAGAGG 
               
               
                   
               
               
                 GAGCAGTTTGAAAAAATAAGCAGTGCTGATCCTTCAGGAGCCTTCCGGAT 
               
               
                   
               
               
                 GCTGAGCACAGCCTACGAGCAGTCAGCCCAGGCTGCTCAGCAGGTCTCCG 
               
               
                   
               
               
                 ACAGCTCGCGCCTTTTGGACCAGCTCAGGGACAGCCGGAGAGAGGCAGAG 
               
               
                   
               
               
                 AGGCTGGTGCGGCAGGCGGGAGGAGGAGGAGGCACCGGCAGCCCCAAGCT 
               
               
                   
               
               
                 TGTGGCCCTGAGGCTGGAGATGTCTTCGTTGCCTGACCTGACACCCACCT 
               
               
                   
               
               
                 TCAACAAGCTCTGTGGCAACTCCAGGCAGATGGCTTGCACCCCAATATCA 
               
               
                   
               
               
                 TGCCCTGGTGAGCTATGTCCCCAAGACAATGGCACAGCCTGTGGCTCCCG 
               
               
                   
               
               
                 CTGCAGGGGTGTCCTTCCCAGGGCCGGTGGGGCCTTCTTGATGGCGGGGC 
               
               
                   
               
               
                 AGGTGGCTGAGCAGCTGCGGGGCTTCAATGCCCAGCTCCAGCGGACCAGG 
               
               
                   
               
               
                 CAGATGATTAGGGCAGCCGAGGAATCTGCCTCACAGATTCAATCCAGTGC 
               
               
                   
               
               
                 CCAGCGCTTGGAGACCCAGGTGAGCGCCAGCCGCTCCCAGATGGAGGAAG 
               
               
                   
               
               
                 ATGTCAGACGCACACGGCTCCTAATCCAGCAGGTCCGGGACTTCCTAACA 
               
               
                   
               
               
                 GACCCCGACACTGATGCAGCCACTATCCAGGAGGTCAGCGAGGCCGTGCT 
               
               
                   
               
               
                 GGCCCTGTGGCTGCCCACAGACTCAGCTACTGTTCTGCAGAAGATGAATG 
               
               
                   
               
               
                 AGATCCAGGCCATTGCAGCCAGGCTCCCCAACGTGGACTTGGTGCTGTCC 
               
               
                   
               
               
                 CAGACCAAGCAGGACATTGCGCGTGCCCGCCGGTTGCAGGCTGAGGCTGA 
               
               
                   
               
               
                 GGAAGCCAGGAGCCGAGCCCATGCAGTGGAGGGCCAGGTGGAAGATGTGG 
               
               
                   
               
               
                 TTGGGAACCTGCGGCAGGGGACAGTGGCACTGCAGGAAGCTCAGGACACC 
               
               
                   
               
               
                 ATGCAAGGCACCAGCCGCTCCCTTCGGCTTATCCAGGACAGGGTTGCTGA 
               
               
                   
               
               
                 GGTTCAGCAGGTACTGCGGCCAGCAGAAAAGCTGGTGACAAGCATGACCA 
               
               
                   
               
               
                 AGCAGCTGGGTGACTTCTGGACACGGATGGAGGAGCTCCGCCACCAAGCC 
               
               
                   
               
               
                 CGGCAGCAGGGGGCAGAGGCAGTCCAGGCCCAGCAGCTTGCGGAAGGTGC 
               
               
                   
               
               
                 CAGCGAGCAGGCATTGAGTGCCCAAGAGGGATTTGAGAGAATAAAACAAA 
               
               
                   
               
               
                 AGTATGCTGAGTTGAAGGACCGGTTGGGTCAGAGTTCCATGCTGGGTGAG 
               
               
                   
               
               
                 CAGGGTGCCCGGATCCAGAGTGTGAAGACAGAGGCAGAGGAGCTGTTTGG 
               
               
                   
               
               
                 GGAGACCATGGAGATGATGGACAGGATGAAAGACATGGAGTTGGAGCTGC 
               
               
                   
               
               
                 TGCGGGGCAGCCAGGCCATCATGCTGCGCTCAGCGGACCTGACAGGACTG 
               
               
                   
               
               
                 GAGAAGCGTGTGGAGCAGATCCGTGACCACATCAATGGGCGCGTGCTCTA 
               
               
                   
               
               
                 CTATGCCACCTGCAAGTGA 
               
            
           
         
       
     
     The protein sequence is: 
     
       
         
           
               
            
               
                 (SEQ ID NO: 6) 
               
               
                 MRPFFLLCFALPGLLHAQQACSRGACYPPVGDLLVGRTRFLRASSTCGLT 
               
               
                   
               
               
                 KPETYCTQYGEWQMKCCKCDSRQPHNYYSHRVENVASSSGPMRWWQSQND 
               
               
                   
               
               
                 VNPVSLQLDLDRRFQLQEVMMEFQGPMPAGMLIERSSDFGKTWRVYQYLA 
               
               
                   
               
               
                 ADCTSTFPRVRQGRPQSWQDVRCQSLPQRPNARLNGGKVQLNLMDLVSGI 
               
               
                   
               
               
                 PATQSQKIQEVGEITNLRVNFTRLAPVPQRGYHPPSAYYAVSQLRLQGSC 
               
               
                   
               
               
                 FCHGHADRCAPKPGASAGPSTAVQVHDVCVCQHNTAGPNCERCAPFYNNR 
               
               
                   
               
               
                 PWRPAEGQDAHECQRCDCNGHSETCHFDPAVFAASQGAYGGVCDNCRDHT 
               
               
                   
               
               
                 EGKNCERCQLHYFRNRRPGASIQETCISCECDPDGAVPGAPCDPVTGQCV 
               
               
                   
               
               
                 CKEHVQGERCDLCKPGFTGLTYANPQGCHRCDCNILGSRRDMPCDEESGR 
               
               
                   
               
               
                 CLCLPNVVGPKCDQCAPYHWKLASGQGCEPCACDPHNSLSPQCNQFTGQC 
               
               
                   
               
               
                 PCREGFGGLMCSAAAIRQCPDRTYGDVATGCRACDCDFRGTEGPGCDKAS 
               
               
                   
               
               
                 GRCLCRPGLTGPRCDQCQRGYCNRYPVCVACHPCFQTYDADLREQALRFG 
               
               
                   
               
               
                 RLRNATASLWSGPGLEDRGLASRILDAKSKIEQIRAVLSSPAVTEQEVAQ 
               
               
                   
               
               
                 VASAILSLRRTLQGLQLDLPLEEETLSLPRDLESLDRSFNGLLTMYQRKR 
               
               
                   
               
               
                 EQFEKISSADPSGAFRMLSTAYEQSAQAAQQVSDSSRLLDQLRDSRREAE 
               
               
                   
               
               
                 RLVRQAGGGGGTGSPKLVALRLEMSSLPDLTPTFNKLCGNSRQMACTPIS 
               
               
                   
               
               
                 CPGELCPQDNGTACGSRCRGVLPRAGGAFLMAGQVAEQLRGFNAQLQRTR 
               
               
                   
               
               
                 QMIRAAEESASQIQSSAQRLETQVSASRSQMEEDVRRTRLLIQQVRDFLT 
               
               
                   
               
               
                 DPDTDAATIQEVSEAVLALWLPTDSATVLQKMNEIQAIAARLPNVDLVLS 
               
               
                   
               
               
                 QTKQDIARARRLQAEAEEARSRAHAVEGQVEDVVGNLRQGTVALQEAQDT 
               
               
                   
               
               
                 MQGTSRSLRLIQDRVAEVQQVLRPAEKLVTSMTKQLGDFWTRMEELRHQA 
               
               
                   
               
               
                 RQQGAEAVQAQQLAEGASEQALSAQEGFERIKQKYAELKDRLGQSSMLGE 
               
               
                   
               
               
                 QGARIQSVKTEAEELFGETMEMMDRMKDMELELLRGSQAIMLRSADLTGL 
               
               
                   
               
               
                 EKRVEQIRDHINGRVLYYATCK 
               
            
           
         
       
     
     Preferably, the LAMA3 (α3 chain of laminin 5) is characterized by the sequence disclosed in the NCBI Data Bank with the Accession no.: NP_937762.1. Its cDNA sequence is: 
     
       
         
           
               
            
               
                 (SEQ ID NO: 7) 
               
               
                 ATGGCGGCGGCCGCGCGGCCTCGGGGTCGGGCACTGGGGCCAGTACTGCC 
               
               
                   
               
               
                 GCCGACGCCGCTGCTCCTGCTGGTACTGCGGGTGCTGCCAGCCTGCGGGG 
               
               
                   
               
               
                 CGACCGCTCGGGATCCCGGGGCCGCGGCCGGGCTCAGCCTTCACCCGACT 
               
               
                   
               
               
                 TACTTCAACCTGGCCGAGGCGGCGAGGATTTGGGCCACCGCCACCTGCGG 
               
               
                   
               
               
                 GGAGAGGGGACCCGGCGAGGGGAGGCCCCAGCCCGAGCTCTACTGCAAGT 
               
               
                   
               
               
                 TGGTCGGGGGCCCCACCGCCCCAGGCAGCGGCCACACCATCCAGGGCCAG 
               
               
                   
               
               
                 TTCTGTGACTATTGCAATTCTGAAGACCCCAGGAAAGCACATCCTGTCAC 
               
               
                   
               
               
                 CAATGCCATCGATGGATCTGAACGTTGGTGGCAAAGCCCTCCCCTGTCCT 
               
               
                   
               
               
                 CAGGCACACAGTACAACAGAGTCAACCTCACCTTGGATCTGGGGCAGCTC 
               
               
                   
               
               
                 TTCCATGTGGCCTATATTTTAATCAAATTTGCAAATTCTCCTCGCCCTGA 
               
               
                   
               
               
                 TCTTTGGGTCTTGGAAAGATCTGTAGACTTTGGAAGCACCTACTCACCAT 
               
               
                   
               
               
                 GGCAATATTTTGCTCATTCTAAAGTAGACTGTTTAAAAGAATTTGGGCGG 
               
               
                   
               
               
                 GAGGCAAATATGGCTGTCACCCGGGATGATGATGTACTTTGTGTTACTGA 
               
               
                   
               
               
                 ATATTCCCGTATTGTACCTTTGGAAAATGGTGAGGTTGTGGTGTCCTTGA 
               
               
                   
               
               
                 TAAACGGTCGTCCAGGTGCAAAAAATTTTACTTTCTCTCACACCCTGAGG 
               
               
                   
               
               
                 GAGTTTACCAAGGCAACAAACATCCGCTTGCGTTTTCTTAGAACCAATAC 
               
               
                   
               
               
                 GCTTCTTGGACACCTCATCTCCAAAGCCCAGCGAGATCCAACTGTCACTC 
               
               
                   
               
               
                 GGCGGTATTATTACAGCATAAAGGACATCAGCATTGGTGGGCAGTGTGTT 
               
               
                   
               
               
                 TGCAATGGCCATGCTGAAGTGTGCAATATAAACAATCCTGAAAAACTGTT 
               
               
                   
               
               
                 TCGGTGTGAATGCCAGCACCACACCTGTGGGGAGACGTGTGATCGCTGCT 
               
               
                   
               
               
                 GCACAGGGTACAATCAGAGGCGCTGGCGGCCCGCCGCTTGGGAGCAGAGC 
               
               
                   
               
               
                 CACGAGTGTGAAGCATGCAACTGCCACGGCCATGCCAGCAACTGTTACTA 
               
               
                   
               
               
                 TGATCCAGATGTTGAGCGGCAGCAGGCAAGCTTGAATACCCAGGGCATCT 
               
               
                   
               
               
                 ATGCTGGTGGAGGGGTCTGCATTAACTGTCAGCACAACACAGCTGGAGTA 
               
               
                   
               
               
                 AACTGTGAACAGTGTGCTAAGGGCTATTACCGCCCTTATGGGGTTCCAGT 
               
               
                   
               
               
                 GGATGCCCCTGATGGCTGCATCCCCTGCAGCTGTGACCCTGAGCATGCGG 
               
               
                   
               
               
                 ATGGCTGTGAACAGGGTTCAGGCCGCTGTCACTGCAAGCCAAATTTCCAC 
               
               
                   
               
               
                 GGAGACAACTGTGAGAAGTGTGCAATTGGATACTACAATTTCCCATTTTG 
               
               
                   
               
               
                 CTTGAGAATTCCCATTTTTCCTGTTTCTACACCAAGTTCAGAAGATCCAG 
               
               
                   
               
               
                 TAGCTGGAGATATAAAAGGGTGTGACTGTAATCTGGAAGGTGTTCTCCCT 
               
               
                   
               
               
                 GAAATATGTGATGCCCACGGACGGTGCCTGTGCCGCCCTGGGGTTGAGGG 
               
               
                   
               
               
                 CCCTCGATGTGATACCTGCCGCTCTGGTTTCTACTCATTCCCTATTTGCC 
               
               
                   
               
               
                 AAGCCTGCTGGTGTTCAGCCCTTGGATCCTACCAGATGCCCTGCAGCTCA 
               
               
                   
               
               
                 GTGACTGGACAGTGTGAATGTCGGCCAGGAGTTACAGGACAGCGGTGTGA 
               
               
                   
               
               
                 CAGGTGTCTCTCAGGAGCTTATGATTTCCCCCACTGCCAAGGTTCCAGCA 
               
               
                   
               
               
                 GTGCTTGTGACCCAGCTGGTACCATCAACTCCAATTTGGGGTATTGCCAA 
               
               
                   
               
               
                 TGCAAGCTTCATGTTGAAGGTCCTACTTGTAGCCGCTGCAAACTGTTATA 
               
               
                   
               
               
                 TTGGAATCTGGACAAAGAAAACCCCAGTGGATGTTCAGAATGCAAGTGCC 
               
               
                   
               
               
                 ATAAGGCGGGAACAGTGAGTGGAACTGGAGAGTGTAGGCAGGGAGATGGT 
               
               
                   
               
               
                 GACTGTCACTGCAAGTCCCATGTGGGTGGCGATTCCTGCGACACCTGTGA 
               
               
                   
               
               
                 AGATGGATATTTTGCTTTGGAAAAGAGCAATTACTTTGGGTGTCAAGGGT 
               
               
                   
               
               
                 GTCAGTGTGACATTGGTGGGGCATTGTCCTCCATGTGCAGTGGGCCCTCG 
               
               
                   
               
               
                 GGAGTGTGCCAGTGCCGAGAGCATGTCGTGGGAAAGGTGTGCCAGCGGCC 
               
               
                   
               
               
                 TGAAAACAACTACTATTTCCCAGATTTGCATCATATGAAGTATGAGATTG 
               
               
                   
               
               
                 AAGACGGCAGCACACCTAATGGGAGAGACCTTCGATTTGGATTTGATCCG 
               
               
                   
               
               
                 CTGGCATTTCCTGAGTTTAGCTGGAGAGGATATGCCCAAATGACCTCAGT 
               
               
                   
               
               
                 ACAGAATGATGTAAGAATAACATTGAATGTAGGGAAGTCAAGTGGCTCCT 
               
               
                   
               
               
                 TGTTTCGTGTTATTCTGAGATACGTTAACCCTGGAACTGAAGCAGTATCT 
               
               
                   
               
               
                 GGCCATATAACTATTTATCCATCCTGGGGTGCTGCTCAAAGCAAAGAGAT 
               
               
                   
               
               
                 CATCTTCCTGCCGAGTAAGGAGCCAGCCTTTGTCACTGTCCCTGGAAATG 
               
               
                   
               
               
                 GTTTTGCAGACCCATTTTCAATCACACCAGGAATATGGGTTGCTTGTATT 
               
               
                   
               
               
                 AAGGCAGAAGGAGTCCTTCTGGATTACCTGGTGCTGCTCCCCAGGGACTA 
               
               
                   
               
               
                 CTATGAAGCCTCTGTACTGCAGCTGCCAGTCACAGAACCATGTGCCTACG 
               
               
                   
               
               
                 CAGGACCTCCCCAAGAAAATTGCTTACTCTACCAGCATTTGCCAGTGACC 
               
               
                   
               
               
                 AGATTCCCCTGTACCCTGGCTTGTGAGGCCAGACACTTCCTGCTTGATGG 
               
               
                   
               
               
                 GGAGCCAAGACCCGTGGCAGTGAGGCAGCCCACACCTGCACACCCTGTCA 
               
               
                   
               
               
                 TGGTGGACCTCAGCGGGAGAGAGGTGGAATTGCATCTGCGGCTGCGCATC 
               
               
                   
               
               
                 CCACAGGTTGGCCACTACGTGGTTGTGGTCGAGTATTCCACGGAGGCAGC 
               
               
                   
               
               
                 TCAGCTGTTTGTGGTTGATGTGAATGTGAAGAGCTCCGGGTCTGTTCTGG 
               
               
                   
               
               
                 CAGGCCAGGTGAACATTTACAGCTGCAACTACAGTGTTCTCTGCCGGAGT 
               
               
                   
               
               
                 GCTGTGATTGATCACATGAGCCGCATCGCCATGTATGAGCTATTGGCAGA 
               
               
                   
               
               
                 TGCAGACATTCAGCTCAAGGGACACATGGCCCGATTCCTTCTGCATCAAG 
               
               
                   
               
               
                 TTTGTATCATACCTATTGAAGAATTCTCAGCTGAGTATGTGAGACCACAA 
               
               
                   
               
               
                 GTCCACTGCATTGCCAGTTATGGGCGATTTGTCAATCAAAGTGCCACCTG 
               
               
                   
               
               
                 TGTCTCCTTGGCCCATGAAACTCCTCCAACAGCATTAATTTTGGATGTTC 
               
               
                   
               
               
                 TAAGTGGCAGGCCTTTCCCTCACCTGCCCCAGCAGTCGTCACCTTCTGTT 
               
               
                   
               
               
                 GATGTTCTTCCTGGGGTCACCTTGAAGGCACCGCAGAATCAAGTGACCCT 
               
               
                   
               
               
                 GAGAGGACGTGTACCACACCTGGGCCGATACGTCTTTGTCATCCATTTTT 
               
               
                   
               
               
                 ACCAAGCAGCGCACCCGACGTTTCCCGCGCAGGTGTCGGTGGATGGCGGG 
               
               
                   
               
               
                 TGGCCACGGGCAGGCTCCTTCCATGCCTCTTTTTGCCCCCATGTGCTTGG 
               
               
                   
               
               
                 CTGCCGGGATCAAGTGATTGCCGAAGGCCAGATTGAGTTTGACATCTCAG 
               
               
                   
               
               
                 AGCCTGAAGTGGCCGCAACTGTGAAGGTTCCAGAAGGAAAGTCCTTGGTT 
               
               
                   
               
               
                 TTGGTCCGTGTTCTAGTGGTGCCTGCAGAAAACTATGACTACCAAATACT 
               
               
                   
               
               
                 TCACAAAAAATCCATGGACAAGTCACTCGAGTTTATCACCAATTGTGGAA 
               
               
                   
               
               
                 AAAACAGCTTTTACCTTGACCCCCAGACAGCCTCCAGATTCTGTAAGAAT 
               
               
                   
               
               
                 TCCGCCAGGTCCCTGGTGGCCTTTTACCACAAGGGCGCCCTGCCTTGTGA 
               
               
                   
               
               
                 GTGCCACCCCACTGGGGCCACCGGCCCTCACTGCAGCCCTGAGGGTGGGC 
               
               
                   
               
               
                 AGTGCCCATGCCAGCCCAACGTCATCGGGCGGCAGTGCACCCGCTGTGCA 
               
               
                   
               
               
                 ACAGGCCACTACGGATTCCCACGCTGCAAGCCGTGCAGCTGTGGTCGGCG 
               
               
                   
               
               
                 CCTTTGTGAAGAGATGACGGGGCAGTGCCGCTGCCCTCCCCGCACGGTCA 
               
               
                   
               
               
                 GGCCCCAGTGTGAGGTGTGTGAGACACACTCATTCAGCTTCCACCCCATG 
               
               
                   
               
               
                 GCCGGCTGCGAAGGCTGCAACTGTTCCAGGAGGGGCACCATCGAGGCTGC 
               
               
                   
               
               
                 CATGCCGGAGTGTGACCGGGACAGCGGGCAGTGCAGATGCAAGCCCAGAA 
               
               
                   
               
               
                 TCACAGGGCGGCAGTGTGACCGATGTGCTTCCGGGTTTTACCGCTTTCCT 
               
               
                   
               
               
                 GAGTGTGTTCCCTGCAATTGCAACAGAGATGGGACTGAGCCAGGAGTGTG 
               
               
                   
               
               
                 TGACCCAGGGACCGGGGCTTGCCTCTGCAAGGAAAATGTAGAAGGCACAG 
               
               
                   
               
               
                 AGTGTAATGTGTGTCGAGAAGGCTCATTCCATTTGGACCCAGCCAATCTC 
               
               
                   
               
               
                 AAGGGTTGTACCAGCTGTTTCTGTTTTGGAGTAAATAATCAATGTCACAG 
               
               
                   
               
               
                 CTCACATAAGCGAAGGACTAAGTTTGTGGATATGCTGGGCTGGCACCTGG 
               
               
                   
               
               
                 AGACAGCAGACAGAGTGGACATCCCTGTCTCTTTCAACCCAGGCAGCAAC 
               
               
                   
               
               
                 AGTATGGTGGCGGATCTCCAGGAGCTGCCCGCAACCATCCACAGCGCGTC 
               
               
                   
               
               
                 CTGGGTCGCACCCACCTCCTACCTGGGGGACAAGGTTTCTTCATATGGTG 
               
               
                   
               
               
                 GTTACCTCACTTACCAAGCCAAGTCCTTTGGCTTGCCTGGCGACATGGTT 
               
               
                   
               
               
                 CTTCTGGAAAAGAAGCCGGATGTACAGCTCACTGGTCAGCACATGTCCAT 
               
               
                   
               
               
                 CATCTATGAGGAGACAAACACCCCACGGCCAGACCGGCTGCATCATGGAC 
               
               
                   
               
               
                 GAGTGCACGTGGTCGAGGGAAACTTCAGACATGCCAGCAGCCGTGCCCCA 
               
               
                   
               
               
                 GTGTCTAGGGAGGAGCTGATGACAGTGCTGTCTAGACTGGCAGATGTGCG 
               
               
                   
               
               
                 CATCCAAGGCCTCTACTTCACAGAGACTCAAAGGCTCACCCTGAGCGAGG 
               
               
                   
               
               
                 TGGGGCTAGAGGAAGCCTCTGACACAGGAAGTGGGCGCATAGCACTTGCT 
               
               
                   
               
               
                 GTGGAAATCTGTGCCTGCCCCCCTGCCTACGCTGGTGACTCTTGTCAGGG 
               
               
                   
               
               
                 TTGTAGCCCTGGATACTATCGGGATCATAAAGGCTTGTATACCGGACGGT 
               
               
                   
               
               
                 GTGTTCCCTGCAATTGCAACGGACATTCAAATCAATGCCAGGATGGCTCA 
               
               
                   
               
               
                 GGCATATGTGTTAACTGTCAGCACAACACCGCGGGAGAGCACTGTGAACG 
               
               
                   
               
               
                 CTGCCAGGAGGGCTACTATGGCAACGCCGTCCACGGATCCTGCAGGGCCT 
               
               
                   
               
               
                 GCCCATGTCCTCACACTAACAGCTTTGCCACTGGCTGTGTGGTGAATGGG 
               
               
                   
               
               
                 GGAGACGTGCGGTGCTCCTGCAAAGCTGGGTACACAGGAACACAGTGTGA 
               
               
                   
               
               
                 AAGGTGTGCACCGGGATATTTCGGGAATCCCCAGAAATTCGGAGGTAGCT 
               
               
                   
               
               
                 GCCAACCATGCAGTTGTAACAGCAATGGCCAGCTGGGCAGCTGTCATCCC 
               
               
                   
               
               
                 CTGACTGGAGACTGCATAAACCAAGAACCCAAAGATAGCAGCCCTGCAGA 
               
               
                   
               
               
                 AGAATGTGATGATTGCGACAGCTGTGTGATGACCCTCCTGAACGACCTGG 
               
               
                   
               
               
                 CCACCATGGGCGAGCAGCTCCGCCTGGTCAAGTCTCAGCTGCAGGGCCTG 
               
               
                   
               
               
                 AGTGCCAGCGCAGGGCTTCTGGAGCAGATGAGGCACATGGAGACCCAGGC 
               
               
                   
               
               
                 CAAGGACCTGAGGAATCAGTTGCTCAACTACCGTTCTGCCATTTCAAATC 
               
               
                   
               
               
                 ATGGATCAAAAATAGAAGGCCTGGAAAGAGAACTGACTGATTTGAATCAA 
               
               
                   
               
               
                 GAATTTGAGACTTTGCAAGAAAAGGCTCAAGTAAATTCCAGAAAAGCACA 
               
               
                   
               
               
                 AACATTAAACAACAATGTTAATCGGGCAACACAAAGCGCAAAAGAACTGG 
               
               
                   
               
               
                 ATGTGAAGATTAAAAATGTCATCCGGAATGTGCACATGCTGAACCGGATA 
               
               
                   
               
               
                 AGGACCTGGCAGAAAACCCACCAGGGGGAGAACAATGGGCTTGCTAACAG 
               
               
                   
               
               
                 TATCCGGGATTCTTTAAATGAATACGAAGCCAAACTCAGTGACCTTCGTG 
               
               
                   
               
               
                 CTCGGCTGCAGGAGGCAGCTGCCCAAGCCAAGCAGGCAAATGGCTTGAAC 
               
               
                   
               
               
                 CAAGAAAACGAGAGAGCTTTGGGAGCCATTCAGAGACAAGTGAAAGAAAT 
               
               
                   
               
               
                 AAATTCCCTGCAGAGTGATTTCACCAAGTATCTAACCACTGCAGACTCAT 
               
               
                   
               
               
                 CTTTGTTGCAAACCAACATTGCGCTGCAGCTGATGGAGAAAAGCCAGAAG 
               
               
                   
               
               
                 GAATATGAAAAATTAGCTGCCAGTTTAAATGAAGCAAGACAAGAACTAAG 
               
               
                   
               
               
                 TGACAAAGTAAGAGAACTTTCCAGATCTGCTGGCAAAACATCCCTTGTGG 
               
               
                   
               
               
                 AGGAGGCAGAAAAGCACGCGCGGTCCTTACAAGAGCTGGCAAAGCAGCTG 
               
               
                   
               
               
                 GAAGAGATCAAGAGAAACGCCAGCGGGGATGAGCTGGTGCGCTGTGCTGT 
               
               
                   
               
               
                 GGATGCCGCCACCGCCTACGAGAACATCCTCAATGCCATCAAAGCGGCCG 
               
               
                   
               
               
                 AGGACGCAGCCAACAGGGCTGCCAGTGCATCTGAATCTGCCCTCCAGACA 
               
               
                   
               
               
                 GTGATAAAGGAAGATCTGCCAAGAAAAGCTAAAACCCTGAGTTCCAACAG 
               
               
                   
               
               
                 TGATAAACTGTTAAATGAAGCCAAGATGACACAAAAGAAGCTAAAGCAAG 
               
               
                   
               
               
                 AAGTCAGTCCAGCTCTCAACAACCTACAGCAAACCCTGAATATTGTGACA 
               
               
                   
               
               
                 GTTCAGAAAGAAGTGATAGACACCAATCTCACAACTCTCCGAGATGGTCT 
               
               
                   
               
               
                 TCATGGGATACAGAGAGGTGATATTGATGCTATGATCAGTAGTGCAAAGA 
               
               
                   
               
               
                 GCATGGTCAGAAAGGCCAACGACATCACAGATGAGGTTCTGGATGGGCTC 
               
               
                   
               
               
                 AACCCCATCCAGACAGATGTGGAAAGAATTAAGGACACCTATGGGAGGAC 
               
               
                   
               
               
                 ACAGAACGAAGACTTCAAAAAGGCTCTGACTGATGCAGATAACTCGGTGA 
               
               
                   
               
               
                 ATAAGTTAACCAACAAACTACCTGATCTTTGGCGCAAGATTGAAAGTATC 
               
               
                   
               
               
                 AACCAACAGCTGTTGCCCTTGGGAAACATCTCTGACAACATGGACAGAAT 
               
               
                   
               
               
                 ACGAGAACTAATTCAGCAGGCCAGAGATGCTGCCAGTAAGGTTGCTGTCC 
               
               
                   
               
               
                 CCATGAGGTTCAATGGTAAATCTGGAGTCGAAGTCCGACTGCCAAATGAC 
               
               
                   
               
               
                 CTGGAAGATTTGAAAGGATATACATCTCTGTCCTTGTTTCTCCAAAGGCC 
               
               
                   
               
               
                 CAACTCAAGAGAAAATGGGGGTACTGAGAATATGTTTGTGATGTACCTTG 
               
               
                   
               
               
                 GAAATAAAGATGCCTCCCGGGACTACATCGGCATGGCAGTTGTGGATGGC 
               
               
                   
               
               
                 CAGCTCACCTGTGTCTACAACCTGGGGGACCGTGAGGCTGAACTCCAAGT 
               
               
                   
               
               
                 GGACCAGATCTTGACCAAGAGTGAGACTAAGGAGGCAGTTATGGATCGGG 
               
               
                   
               
               
                 TGAAATTTCAGAGAATTTATCAGTTTGCAAGGCTTAATTACACCAAAGGA 
               
               
                   
               
               
                 GCCACATCCAGTAAACCAGAAACACCCGGAGTCTATGACATGGATGGTAG 
               
               
                   
               
               
                 AAATAGCAATACACTCCTTAATTTGGATCCTGAAAATGTTGTATTTTATG 
               
               
                   
               
               
                 TTGGAGGTTACCCACCTGATTTTAAACTTCCCAGTCGACTAAGTTTCCCT 
               
               
                   
               
               
                 CCATACAAAGGTTGTATTGAATTAGATGACCTCAATGAAAATGTTCTGAG 
               
               
                   
               
               
                 CTTGTACAACTTCAAAAAAACATTCAATCTCAACACAACTGAAGTGGAGC 
               
               
                   
               
               
                 CTTGTAGAAGGAGGAAGGAAGAGTCAGACAAAAATTATTTTGAAGGTACG 
               
               
                   
               
               
                 GGCTATGCTCGAGTTCCAACTCAACCACATGCTCCCATCCCAACCTTTGG 
               
               
                   
               
               
                 ACAGACAATTCAGACCACCGTGGATAGAGGCTTGCTGTTCTTTGCAGAAA 
               
               
                   
               
               
                 ACGGGGATCGCTTCATATCTCTAAATATAGAAGATGGCAAGCTCATGGTG 
               
               
                   
               
               
                 AGATACAAACTGAATTCAGAGCTACCAAAAGAGAGAGGAGTTGGAGACGC 
               
               
                   
               
               
                 CATAAACAACGGCAGAGACCATTCGATTCAGATCAAAATTGGAAAACTCC 
               
               
                   
               
               
                 AAAAGCGTATGTGGATAAATGTGGACGTTCAAAACACTATAATTGATGGT 
               
               
                   
               
               
                 GAAGTATTTGATTTCAGCACATATTATCTGGGAGGAATTCCAATTGCAAT 
               
               
                   
               
               
                 CAGGGAAAGATTTAACATTTCTACGCCTGCTTTCCGAGGCTGCATGAAAA 
               
               
                   
               
               
                 ATTTGAAGAAAACCAGTGGTGTCGTTAGATTGAATGATACTGTGGGAGTA 
               
               
                   
               
               
                 ACCAAAAAGTGCTCGGAAGACTGGAAGCTTGTGCGATCTGCCTCATTCTC 
               
               
                   
               
               
                 CAGAGGAGGACAATTGAGTTTCACTGATTTGGGCTTACCACCTACTGACC 
               
               
                   
               
               
                 ACCTCCAGGCCTCATTTGGATTTCAGACCTTTCAACCCAGTGGCATATTA 
               
               
                   
               
               
                 TTAGATCATCAGACATGGACAAGGAACCTGCAGGTCACTCTGGAAGATGG 
               
               
                   
               
               
                 TTACATTGAATTGAGCACCAGCGATAGCGGCGGCCCAATTTTTAAATCTC 
               
               
                   
               
               
                 CACAGACGTATATGGATGGTTTACTGCATTATGTATCTGTAATAAGCGAC 
               
               
                   
               
               
                 AACTCTGGACTACGGCTTCTCATCGATGACCAGCTTCTGAGAAATAGCAA 
               
               
                   
               
               
                 AAGGCTAAAACACATTTCAAGTTCCCGGCAGTCTCTGCGTCTGGGCGGGA 
               
               
                   
               
               
                 GCAATTTTGAGGGTTGTATTAGCAATGTTTTTGTCCAGAGGTTATCACTG 
               
               
                   
               
               
                 AGTCCTGAAGTCCTAGATTTGACCAGTAACTCTCTCAAGAGAGATGTGTC 
               
               
                   
               
               
                 CCTGGGAGGCTGCAGTTTAAACAAACCACCTTTTCTAATGTTGCTTAAAG 
               
               
                   
               
               
                 GTTCTACCAGGTTTAACAAGACCAAGACTTTTCGTATCAACCAGCTGTTG 
               
               
                   
               
               
                 CAGGACACACCAGTGGCCTCCCCAAGGAGCGTGAAGGTGTGGCAAGATGC 
               
               
                   
               
               
                 TTGCTCACCACTTCCCAAGACCCAGGCCAATCATGGAGCCCTCCAGTTTG 
               
               
                   
               
               
                 GGGACATTCCCACCAGCCACTTGCTATTCAAGCTTCCTCAGGAGCTGCTG 
               
               
                   
               
               
                 AAACCCAGGTCACAGTTTGCTGTGGACATGCAGACAACATCCTCCAGAGG 
               
               
                   
               
               
                 ACTGGTGTTTCACACGGGCACTAAGAACTCCTTTATGGCTCTTTATCTTT 
               
               
                   
               
               
                 CAAAAGGACGTCTGGTCTTTGCACTGGGGACAGATGGGAAAAAATTGAGG 
               
               
                   
               
               
                 ATCAAAAGCAAGGAGAAATGCAATGATGGGAAATGGCACACGGTGGTGTT 
               
               
                   
               
               
                 TGGCCATGATGGGGAAAAGGGGCGCTTGGTTGTGGATGGACTGAGGGCCC 
               
               
                   
               
               
                 GGGAGGGAAGTTTGCCTGGAAACTCCACCATCAGCATCAGAGCGCCAGTT 
               
               
                   
               
               
                 TACCTGGGATCACCTCCATCAGGGAAACCAAAGAGCCTCCCCACAAACAG 
               
               
                   
               
               
                 CTTTGTGGGATGCCTGAAGAACTTTCAGCTGGATTCAAAACCCTTGTATA 
               
               
                   
               
               
                 CCCCTTCTTCAAGCTTCGGGGTGTCTTCCTGCTTGGGTGGTCCTTTGGAG 
               
               
                   
               
               
                 AAAGGCATTTATTTCTCTGAAGAAGGAGGTCATGTCGTCTTGGCTCACTC 
               
               
                   
               
               
                 TGTATTGTTGGGGCCAGAATTTAAGCTTGTTTTCAGCATCCGCCCAAGAA 
               
               
                   
               
               
                 GTCTCACTGGGATCCTAATACACATCGGAAGTCAGCCCGGGAAGCACTTA 
               
               
                   
               
               
                 TGTGTTTACCTGGAGGCAGGAAAGGTCACGGCCTCTATGGACAGTGGGGC 
               
               
                   
               
               
                 AGGTGGGACCTCAACGTCGGTCACACCAAAGCAGTCTCTGTGTGATGGAC 
               
               
                   
               
               
                 AGTGGCACTCGGTGGCAGTCACCATAAAACAACACATCCTGCACCTGGAA 
               
               
                   
               
               
                 CTGGACACAGACAGTAGCTACACAGCTGGACAGATCCCCTTCCCACCTGC 
               
               
                   
               
               
                 CAGCACTCAAGAGCCACTACACCTTGGAGGTGCTCCAGCCAATTTGACGA 
               
               
                   
               
               
                 CACTGAGGATCCCTGTGTGGAAATCATTCTTTGGCTGTCTGAGGAATATT 
               
               
                   
               
               
                 CATGTCAATCACATCCCTGTCCCTGTCACTGAAGCCTTGGAAGTCCAGGG 
               
               
                   
               
               
                 GCCTGTCAGTCTGAATGGTTGTCCTGACCAGTAA 
               
            
           
         
       
     
     Its protein sequence is (3333 aa): 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 8) 
                   
               
               
                 MAAAARPRGRALGPVLPPTPLLLLVLRVLPACGATARDPGAAAGLSLHPTYFNLAEAARIWATATCGERG 
                   
               
               
                   
               
               
                 PGEGRPQPELYCKLVGGPTAPGSGHTIQGQFCDYCNSEDPRKAHPVTNAIDGSERWWQSPPLSSGTQYNR 
               
               
                   
               
               
                 VNLTLDLGQLFHVAYILIKFANSPRPDLWVLERSVDFGSTYSPWQYFAHSKVDCLKEFGREANMAVTRDD 
               
               
                   
               
               
                 DVLCVTEYSRIVPLENGEVVVSLINGRPGAKNFTFSHTLREFTKATNIRLRFLRTNTLLGHLISKAQRDP 
               
               
                   
               
               
                 TVTRRYYYSIKDISIGGQCVCNGHAEVCNINNPEKLFRCECQHHTCGETCDRCCTGYNQRRWRPAAWEQS 
               
               
                   
               
               
                 HECEACNCHGHASNCYYDPDVERQQASLNTQGIYAGGGVCINCQHNTAGVNCEQCAKGYYRPYGVPVDAP 
               
               
                   
               
               
                 DGCIPCSCDPEHADGCEQGSGRCHCKPNFHGDNCEKCAIGYYNFPFCLRIP1FPVSTPSSEDPVAGDIKG 
               
               
                   
               
               
                 CDCNLEGVLPEICDAHGRCLCRPGVEGPRCDTCRSGFYSFPICQACWCSALGSYQMPCSSVTGQCECRPG 
               
               
                   
               
               
                 VTGQRCDRCLSGAYDFPHCQGSSSACDPAGTINSNLGYCQCKLHVEGPTCSRCKLLYWNLDKENPSGCSE 
               
               
                   
               
               
                 CKCHKAGTVSGTGECRQGDGDCHCKSHVGGDSCDTCEDGYFALEKSNYFGCQGCQCDIGGALSSMCSGPS 
               
               
                   
               
               
                 GVCQCREHVVGKVCQRPENNYYFPDLHHMKYEIEDGSTPNGRDLRFGFDPLAFPEFSWRGYAQMTSVQND 
               
               
                   
               
               
                 VRITLNVGKSSGSLFRVILRYVNPGTEAVSGHITIYPSWGAAQSKEIIFLPSKEPAFVTVPGNGFADPFS 
               
               
                   
               
               
                 ITPGIWVACIKAEGVLLDYLVLLPRDYYEASVLQLPVTEPCAYAGPPQENCLLYQHLPVTRFPCTLACEA 
               
               
                   
               
               
                 RHFLLDGEPRPVAVRQPTPAHPVMVDLSGREVELHLRLRIPQVGHYVVVVEYSTEAAQLFVVDVNVKSSG 
               
               
                   
               
               
                 SVLAGQVNIYSCNYSVLCRSAVIDHMSRIAMYELLADADIQLKGHMARFLLHQVCIIPIEEFSAEYVRPQ 
               
               
                   
               
               
                 VHCIASYGRFVNQSATCVSLAHETPPTALILDVLSGRPFPHLPQQSSPSVDVLPGVTLKAPQNQVTLRGR 
               
               
                   
               
               
                 VPHLGRYVFVIHFYQAAHPTFPAQVSVDGGWPRAGSFHASFCPHVLGCRDQVIAEGQIEFDISEPEVAAT 
               
               
                   
               
               
                 VKVPEGKSLVLVRVLVVPAENYDYQILHKKSMDKSLEFITNCGKNSFYLDPQTASRFCKNSARSLVAFYH 
               
               
                   
               
               
                 KGALPCECHPTGATGPHCSPEGGQCPCQPNVIGRQCTRCATGHYGFPRCKPCSCGRRLCEEMTGQCRCPP 
               
               
                   
               
               
                 RTVRPQCEVCETHSFSFHPMAGCEGCNCSRRGTIEAAMPECDRDSGQCRCKPRITGRQCDRCASGFYRFP 
               
               
                   
               
               
                 ECVPCNCNRDGTEPGVCDPGTGACLCKENVEGTECNVCREGSFHLDPANLKGCTSCFCFGVNNQCHSSHK 
               
               
                   
               
               
                 RRTKFVDMLGWHLETADRVDIPVSFNPGSNSMVADLQELPATIHSASWVAPTSYLGDKVSSYGGYLTYQA 
               
               
                   
               
               
                 KSFGLPGDMVLLEKKPDVQLTGQHMSIIYEETNTPRPDRLHHGRVHVVEGNFRHASSRAPVSREELMTVL 
               
               
                   
               
               
                 SRLADVRIQGLYFTETQRLTLSEVGLEEASDTGSGRIALAVEICACPPAYAGDSCQGCSPGYYRDHKGLY 
               
               
                   
               
               
                 TGRCVPCNCNGHSNQCQDGSGICVNCQHNTAGEHCERCQEGYYGNAVHGSCRACPCPHTNSFATGCVVNG 
               
               
                   
               
               
                 GDVRCSCKAGYTGTQCERCAPGYFGNPQKFGGSCQPCSCNSNGQLGSCHPLTGDCINQEPKDSSPAEECD 
               
               
                   
               
               
                 DCDSCVMTLLNDLATMGEQLRLVKSQLQGLSASAGLLEQMRHMETQAKDLRNQLLNYRSAISNHGSKIEG 
               
               
                   
               
               
                 LERELTDLNQEFETLQEKAQVNSRKAQTLNNNVNRATQSAKELDVKIKNVIRNVHILLKQISGTDGEGNN 
               
               
                   
               
               
                 VPSGDFSREWAEAQRMMRELRNRNFGKHLREAEADKRESQLLLNRIRTWQKTHQGENNGLANSIRDSINE 
               
               
                   
               
               
                 YEAKLSDLRARLQEAAAQAKQANGLNQENERALGAIQRQVKEINSLQSDFTKYLTTADSSLLQTNIALQL 
               
               
                   
               
               
                 MEKSQKEYEKLAASLNEARQELSDKVRELSRSAGKTSLVEEAEKHARSLQELAKQLEEIKRNASGDELVR 
               
               
                   
               
               
                 CAVDAATAYENILNAIKAAEDAANRAASASESALQTVIKEDLPRKAKTLSSNSDKLLNEAKMTQKKLKQE 
               
               
                   
               
               
                 VSPALNNLQQTLNIVTVQKEVIDTNLTTLRDGLHGIQRGDIDAMISSAKSMVRKANDITDEVLDGLNPIQ 
               
               
                   
               
               
                 TDVERIKDTYGRTQNEDFKKALTDADNSVNKLTNKLPDLWRKIESINQQLLPLGNISDNMDRIRELIQQA 
               
               
                   
               
               
                 RDAASKVAVPMRFNGKSGVEVRLPNDLEDLKGYTSLSLFLQRPNSRENGGTENMFVMYLGNKDASRDYIG 
               
               
                   
               
               
                 MAVVDGQLTCVYNLGDREAELQVDQILTKSETKEAVMDRVKFQRIYQFARLNYTKGATSSKPETPGVYDM 
               
               
                   
               
               
                 DGRNSNTLLNLDPENVVFYVGGYPPDFKLPSRLSFPPYKGCIELDDLNENVLSLYNFKKTFNLNTTEVEP 
               
               
                   
               
               
                 CRRRKEESDKNYFEGTGYARVPTQPHAPIPTFGQTIQTTVDRGLLFFAENGDRFISLNIEDGKLMVRYKL 
               
               
                   
               
               
                 NSELPKERGVGDAINNGRDHSIQIKIGKLQKRMWINVDVQNTIIDGEVFDFSTYYLGGIPIAIRERFNIS 
               
               
                   
               
               
                 TPAFRGCMKNLKKTSGVVRLNDTVGVTKKCSEDWKLVRSASFSRGGQLSFTDLGLPPTDHLQASFGFQTF 
               
               
                   
               
               
                 QPSGILLDHQTWTRNLQVTLEDGYIELSTSDSGGPIFKSPQTYMDGLLHYVSVISDNSGLRLLIDDQLLR 
               
               
                   
               
               
                 NSKRLKHISSSRQSLRLGGSNFEGCISNVFVQRLSLSPEVLDLTSNSLKRDVSLGGCSLNKPPFLMLLKG 
               
               
                   
               
               
                 STRFNKTKTFRINQLLQDTPVASPRSVKVWQDACSPLPKTQANHGALQFGDIPTSHLLFKLPQELLKPRS 
               
               
                   
               
               
                 QFAVDMQTTSSRGLVFHTGTKNSFMALYLSKGRLVFALGTDGKKLRIKSKEKCNDGKWHTVVFGHDGEKG 
               
               
                   
               
               
                 RLVVDGLRAREGSLPGNSTISIRAPVYLGSPPSGKPKSLPTNSFVGCLKNFQLDSKPLYTPSSSFGVSSC 
               
               
                   
               
               
                 LGGPLEKGIYFSEEGGHVVLAHSVLLGPEFKLVFSIRPRSLTGILIHIGSQPGKHLCVYLEAGKVTASMD 
               
               
                   
               
               
                 SGAGGTSTSVTPKQSLCDGQWHSVAVTIKQHILHLELDTDSSYTAGQIPFPASTQEPLHLGGAPANLTT 
               
               
                   
               
               
                 IRIPVWKSFFGCLRNIHVNHIPVPVTEALEVQGPVSLNGCPDQ 
               
            
           
         
       
     
     Preferably, the LAMC2 (γ2 chain of laminin 5) is characterized by the sequence disclosed in the NCBI Data Bank with the Accession no.: NM_018891. Its cDNA sequence is: 
     
       
         
           
               
            
               
                 (SEQ ID NO: 9) 
               
               
                 ATGCCTGCGCTCTGGCTGGGCTGCTGCCTCTGCTTCTCGCTCCTCCTGCC 
               
               
                   
               
               
                 CGCAGCCCGGGCCACCTCCAGGAGGGAAGTCTGTGATTGCAATGGGAAGT 
               
               
                   
               
               
                 CCAGGCAGTGTATCTTTGATCGGGAACTTCACAGACAAACTGGTAATGGA 
               
               
                   
               
               
                 TTCCGCTGCCTCAACTGCAATGACAACACTGATGGCATTCACTGCGAGAA 
               
               
                   
               
               
                 GTGCAAGAATGGCTTTTACCGGCACAGAGAAAGGGACCGCTGTTTGCCCT 
               
               
                   
               
               
                 GCAATTGTAACTCCAAAGGTTCTCTTAGTGCTCGATGTGACAACTCCGGA 
               
               
                   
               
               
                 CGGTGCAGCTGTAAACCAGGTGTGACAGGAGCCAGATGCGACCGATGTCT 
               
               
                   
               
               
                 GCCAGGCTTCCACATGCTCACGGATGCGGGGTGCACCCAAGACCAGAGAC 
               
               
                   
               
               
                 TGCTAGACTCCAAGTGTGACTGTGACCCAGCTGGCATCGCAGGGCCCTGT 
               
               
                   
               
               
                 GACGCGGGCCGCTGTGTCTGCAAGCCAGCTGTCACTGGAGAACGCTGTGA 
               
               
                   
               
               
                 TAGGTGTCGATCAGGTTACTATAATCTGGATGGGGGGAACCCTGAGGGCT 
               
               
                   
               
               
                 GTACCCAGTGTTTCTGCTATGGGCATTCAGCCAGCTGCCGCAGCTCTGCA 
               
               
                   
               
               
                 GAATACAGTGTCCATAAGATCACCTCTACCTTTCATCAAGATGTTGATGG 
               
               
                   
               
               
                 CTGGAAGGCTGTCCAACGAAATGGGTCTCCTGCAAAGCTCCAATGGTCAC 
               
               
                   
               
               
                 AGCGCCATCAAGATGTGTTTAGCTCAGCCCAACGACTAGACCCTGTCTAT 
               
               
                   
               
               
                 TTTGTGGCTCCTGCCAAATTTCTTGGGAATCAACAGGTGAGCTATGGTCA 
               
               
                   
               
               
                 AAGCCTGTCCTTTGACTACCGTGTGGACAGAGGAGGCAGACACCCATCTG 
               
               
                   
               
               
                 CCCATGATGTGATTCTGGAAGGTGCTGGTCTACGGATCACAGCTCCCTTG 
               
               
                   
               
               
                 ATGCCACTTGGCAAGACACTGCCTTGTGGGCTCACCAAGACTTACACATT 
               
               
                   
               
               
                 CAGGTTAAATGAGCATCCAAGCAATAATTGGAGCCCCCAGCTGAGTTACT 
               
               
                   
               
               
                 TTGAGTATCGAAGGTTACTGCGGAATCTCACAGCCCTCCGCATCCGAGCT 
               
               
                   
               
               
                 ACATATGGAGAATACAGTACTGGGTACATTGACAATGTGACCCTGATTTC 
               
               
                   
               
               
                 AGCCCGCCCTGTCTCTGGAGCCCCAGCACCCTGGGTTGAACAGTGTATAT 
               
               
                   
               
               
                 GTCCTGTTGGGTACAAGGGGCAATTCTGCCAGGATTGTGCTTCTGGCTAC 
               
               
                   
               
               
                 AAGAGAGATTCAGCGAGACTGGGGCCTTTTGGCACCTGTATTCCTTGTAA 
               
               
                   
               
               
                 CTGTCAAGGGGGAGGGGCCTGTGATCCAGACACAGGAGATTGTTATTCAG 
               
               
                   
               
               
                 GGGATGAGAATCCTGACATTGAGTGTGCTGACTGCCCAATTGGTTTCTAC 
               
               
                   
               
               
                 AACGATCCGCACGACCCCCGCAGCTGCAAGCCATGTCCCTGTCATAACGG 
               
               
                   
               
               
                 GTTCAGCTGCTCAGTGATGCCGGAGACGGAGGAGGTGGTGTGCAATAACT 
               
               
                   
               
               
                 GCCCTCCCGGGGTCACCGGTGCCCGCTGTGAGCTCTGTGCTGATGGCTAC 
               
               
                   
               
               
                 TTTGGGGACCCCTTTGGTGAACATGGCCCAGTGAGGCCTTGTCAGCCCTG 
               
               
                   
               
               
                 TCAATGCAACAACAATGTGGACCCCAGTGCCTCTGGGAATTGTGACCGGC 
               
               
                   
               
               
                 TGACAGGCAGGTGTTTGAAGTGTATCCACAACACAGCCGGCATCTACTGC 
               
               
                   
               
               
                 GACCAGTGCAAAGCAGGCTACTTCGGGGACCCATTGGCTCCCAACCCAGC 
               
               
                   
               
               
                 AGACAAGTGTCGAGCTTGCAACTGTAACCCCATGGGCTCAGAGCCTGTAG 
               
               
                   
               
               
                 GATGTCGAAGTGATGGCACCTGTGTTTGCAAGCCAGGATTTGGTGGCCCC 
               
               
                   
               
               
                 AACTGTGAGCATGGAGCATTCAGCTGTCCAGCTTGCTATAATCAAGTGAA 
               
               
                   
               
               
                 GATTCAGATGGATCAGTTTATGCAGCAGCTTCAGAGAATGGAGGCCCTGA 
               
               
                   
               
               
                 TTTCAAAGGCTCAGGGTGGTGATGGAGTAGTACCTGATACAGAGCTGGAA 
               
               
                   
               
               
                 GGCAGGATGCAGCAGGCTGAGCAGGCCCTTCAGGACATTCTGAGAGATGC 
               
               
                   
               
               
                 CCAGATTTCAGAAGGTGCTAGCAGATCCCTTGGTCTCCAGTTGGCCAAGG 
               
               
                   
               
               
                 TGAGGAGCCAAGAGAACAGCTACCAGAGCCGCCTGGATGACCTCAAGATG 
               
               
                   
               
               
                 ACTGTGGAAAGAGTTCGGGCTCTGGGAAGTCAGTACCAGAACCGAGTTCG 
               
               
                   
               
               
                 GGATACTCACAGGCTCATCACTCAGATGCAGCTGAGCCTGGCAGAAAGTG 
               
               
                   
               
               
                 AAGCTTCCTTGGGAAACACTAACATTCCTGCCTCAGACCACTACGTGGGG 
               
               
                   
               
               
                 CCAAATGGCTTTAAAAGTCTGGCTCAGGAGGCCACAAGATTAGCAGAAAG 
               
               
                   
               
               
                 CCACGTTGAGTCAGCCAGTAACATGGAGCAACTGACAAGGGAAACTGAGG 
               
               
                   
               
               
                 ACTATTCCAAACAAGCCCTCTCACTGGTGCGCAAGGCCCTGCATGAAGGA 
               
               
                   
               
               
                 GTCGGAAGCGGAAGCGGTAGCCCGGACGGTGCTGTGGTGCAAGGGCTTGT 
               
               
                   
               
               
                 GGAAAAATTGGAGAAAACCAAGTCCCTGGCCCAGCAGTTGACAAGGGAGG 
               
               
                   
               
               
                 CCACTCAAGCGGAAATTGAAGCAGATAGGTCTTATCAGCACAGTCTCCGC 
               
               
                   
               
               
                 CTCCTGGATTCAGTGTCTCGGCTTCAGGGAGTCAGTGATCAGTCCTTTCA 
               
               
                   
               
               
                 GGTGGAAGAAGCAAAGAGGATCAAACAAAAAGCGGATTCACTCTCAAGCC 
               
               
                   
               
               
                 TGGTAACCAGGCATATGGATGAGTTCAAGCGTACACAGAAGAATCTGGGA 
               
               
                   
               
               
                 AACTGGAAAGAAGAAGCACAGCAGCTCTTACAGAATGGAAAAAGTGGGAG 
               
               
                   
               
               
                 AGAGAAATCAGATCAGCTGCTTTCCCGTGCCAATCTTGCTAAAAGCAGAG 
               
               
                   
               
               
                 CACAAGAAGCACTGAGTATGGGCAATGCCACTTTTTATGAAGTTGAGAGC 
               
               
                   
               
               
                 ATCCTTAAAAACCTCAGAGAGTTTGACCTGCAGGTGGACAACAGAAAAGC 
               
               
                   
               
               
                 AGAAGCTGAAGAAGCCATGAAGAGACTCTCCTACATCAGCCAGAAGGTTT 
               
               
                   
               
               
                 CAGATGCCAGTGACAAGACCCAGCAAGCAGAAAGAGCCCTGGGGAGCGCT 
               
               
                   
               
               
                 GCTGCTGATGCACAGAGGGCAAAGAATGGGGCCGGGGAGGCCCTGGAAAT 
               
               
                   
               
               
                 CTCCAGTGAGATTGAACAGGAGATTGGGAGTCTGAACTTGGAAGCCAATG 
               
               
                   
               
               
                 TGACAGCAGATGGAGCCTTGGCCATGGAAAAGGGACTGGCCTCTCTGAAG 
               
               
                   
               
               
                 AGTGAGATGAGGGAAGTGGAAGGAGAGCTGGPAAGGAAGGAGCTGGAGTT 
               
               
                   
               
               
                 TGACACGAATATGGATGCAGTACAGATGGTGATTACAGAAGCCCAGAAGG 
               
               
                   
               
               
                 TTGATACCAGAGCCAAGAACGCTGGGGTTACAATCCAAGACACACTCAAC 
               
               
                   
               
               
                 ACATTAGACGGCCTCCTGCATCTGATGGGTATGTGA 
               
            
           
         
       
     
     Its protein sequence is: 
     
       
         
           
               
            
               
                 (SEQ ID NO: 10) 
               
               
                 MPALWLGCCLCFSLLLPAARATSRREVCDCNGKSRQCIFDRELHRQTGNG 
               
               
                   
               
               
                 FRCLNCNDNTDGIHCEKCKNGFYRHRERDRCLPCNCNSKGSLSARCDNSG 
               
               
                   
               
               
                 RCSCKPGVTGARCDRCLPGFHMLTDAGCTQDQRLLDSKCDCDPAGIAGPC 
               
               
                   
               
               
                 DAGRCVCKPAVTGERCDRCRSGYYNLDGGNPEGCTQCFCYGHSASCRSSA 
               
               
                   
               
               
                 EYSVHKITSTFHQDVDGWKAVQRNGSPAKLQWSQRHQDVFSSAQRLDPVY 
               
               
                   
               
               
                 FVAPAKFLGNQQVSYGQSLSFDYRVDRGGRHPSAHDVILEGAGLRITAPL 
               
               
                   
               
               
                 MPLGKTLPCGLTKTYTFRLNEHPSNNWSPQLSYFEYRRLLRNLTALRIRA 
               
               
                   
               
               
                 TYGEYSTGYIDNVTLISARPVSGAPAPWVEQCICPVGYKGQFCQDCASGY 
               
               
                   
               
               
                 KRDSARLGPFGTCIPCNCQGGGACDPDTGDCYSGDENPDIECADCPIGFY 
               
               
                   
               
               
                 NDPHDPRSCKPCPCHNGFSCSVMPETEEVVCNNCPPGVTGARCELCADGY 
               
               
                   
               
               
                 FGDPFGEHGPVRPCQPCQCNNNVDPSASGNCDRLTGRCLKCIHNTAGIYC 
               
               
                   
               
               
                 DQCKAGYFGDPLAPNPADKCRACNCNPMGSEPVGCRSDGTCVCKPGFGGP 
               
               
                   
               
               
                 NCEHGAFSCPACYNQVKIQMDQFMQQLQRMEALISKAQGGDGVVPDTELE 
               
               
                   
               
               
                 GRMQQAEQALQDILRDAQISEGASRSLGLQLAKVRSQENSYQSRLDDLKM 
               
               
                   
               
               
                 TVERVRALGSQYQNRVRDTHRLITQMQLSLAESEASLGNTNIPASDHYVG 
               
               
                   
               
               
                 PNGFKSLAQEATRLAESHVESASNMEQLTRETEDYSKQALSLVRKALHEG 
               
               
                   
               
               
                 VGSGSGSPDGAVVQGLVEKLEKTKSLAQQLTREATQAEIEADRSYQHSLR 
               
               
                   
               
               
                 LLDSVSRLQGVSDQSFQVEEAKRIKQKADSLSSLVTRHMDEFKRTQKNLG 
               
               
                   
               
               
                 NWKEEAQQLLQNGKSGREKSDQLLSRANLAKSRAQEALSMGNATFYEVES 
               
               
                   
               
               
                 ILKNLREFDLQVDNRKAEAEEAMKRLSYISQKVSDASDKTQQAERALGSA 
               
               
                   
               
               
                 AADAQRAKNGAGEALEISSEIEQEIGSLNLEANVTADGALAMEKGLASLK 
               
               
                   
               
               
                 SEMREVEGELERKELEFDTNMDAVQMVITEAQKVDTRAKNAGVTIQDTLN 
               
               
                   
               
               
                 TLDGLLHLMGM 
               
            
           
         
       
     
     Included in the present invention are also nucleic acid sequences derived from the sequences shown below, e.g. functional fragments, mutants, derivatives, analogues, and sequences having a % of identity of at least 70% with the below sequences. 
     In the context of the present invention, the cDNA, the gene, the mRNA, the polynucleotide or the protein encoded therefrom herein mentioned comprise also their functional fragments, functional analogous, derivatives, variants, isoforms, orthologues or homologous, splicing variants, functional mutants, etc. 
     The term gene (or cDNA) herein also includes corresponding orthologous or homologous genes, isoforms, variants, allelic variants, functional derivatives, functional fragments thereof. The expression “protein” is intended to include also the corresponding protein encoded from a corresponding orthologous or homologous genes, functional mutants, functional derivatives, functional fragments or analogues, isoforms thereof. 
     In the context of the present invention, the term “polypeptide” or “protein” includes:
         i. the whole protein, allelic variants and orthologs thereof;   ii. any synthetic, recombinant or proteolytic functional fragment;   iii. any functional equivalent, such as, for example, synthetic or recombinant functional analogues.       

     In the present invention “functional mutants” of the protein are mutants that may be generated by mutating one or more amino acids in their sequences and that maintain their activity. Indeed, in the present invention the protein encoded by the transgene, if required, can be modified in vitro and/or in vivo, for example by glycosylation, myristoylation, amidation, carboxylation or phosphorylation, and may be obtained, for example, by synthetic or recombinant techniques known in the art. The term “derivative” as used herein in relation to a protein means a chemically modified peptide or an analogue thereof, wherein at least one substituent is not present in the unmodified peptide or an analogue thereof, i.e. a peptide which has been covalently modified. Typical modifications are amides, carbohydrates, alkyl groups, acyl groups, esters and the like. As used herein, the term “derivatives” also refers to longer or shorter polypeptides having e.g. a percentage of identity of at least 41% , preferably at least 41.5%, 50%, 54.9% , 60%, 61.2%, 64.1%, 65%, 70% or 75%, more preferably of at least 85%, as an example of at least 90%, and even more preferably of at least 95% with the herein disclosed genes and sequences, or with an amino acid sequence of the correspondent region encoded from orthologous or homologous gene thereof. The term “analogue” as used herein referring to a protein means a modified peptide wherein one or more amino acid residues of the peptide have been substituted by other amino acid residues and/or wherein one or more amino acid residues have been deleted from the peptide and/or wherein one or more amino acid residues have been deleted from the peptide and or wherein one or more amino acid residues have been added to the peptide. Such addition or deletion of amino acid residues can take place at the N-terminal of the peptide and/or at the C-terminal of the peptide. A “derivative” may be a nucleic acid molecule, as a DNA molecule, coding the polynucleotide as above defined, or a nucleic acid molecule comprising the polynucleotide as above defined, or a polynucleotide of complementary sequence. In the context of the present invention the term “derivatives” also refers to longer or shorter polynucleotides and/or polynucleotides having e.g. a percentage of identity of at least 41% , 50%, 60%, 65%, 70% or 75%, more preferably of at least 85%, as an example of at least 90%, and even more preferably of at least 95% or 100% with the sequences herein discloses or with their complementary sequence or with their DNA or RNA corresponding sequence. The term “derivatives” and the term “polynucleotide” also include modified synthetic oligonucleotides. The modified synthetic oligonucleotide are preferably LNA (Locked Nucleic Acid), phosphoro-thiolated oligos or methylated oligos, morpholinos, 2′-O-methyl, 2′-O-methoxyethyl oligonucleotides and cholesterol-conjugated 2′-O-methyl modified oligonucleotides (antagomirs). The term “derivative” may also include nucleotide analogues, i.e. a naturally occurring ribonucleotide or deoxyribonucleotide substituted by a non-naturally occurring nucleotide. The term “derivatives” also includes nucleic acids or polypeptides that may be generated by mutating one or more nucleotide or amino acid in their sequences, equivalents or precursor sequences. The term “derivatives” also includes at least one functional fragment of the polynucleotide. In the context of the present invention “functional” is intended for example as “maintaining their activity”. As used herein “fragments” refers to polynucleotides having preferably a length of at least 1000 nucleotides, 1100 nucleotide, 1200 nucleotides, 1300 nucleotides, 1400 nucleotides, 1500 nucleotides or to polypeptide having preferably a length of at least 50 aa, 100 aa, 150 aa, 200 aa, 250 aa, 300 aa, . . . . The term “polynucleotide” also refers to modified polynucleotides. 
     The term “functional fragment” or “functional derivative” may be understood as maintaining the same activity of the protein. “Derivatives” may be recombinant or synthetic. The term “derivative” as used herein in relation to a protein means a chemically modified protein or an analogue thereof, wherein at least one substituent is not present in the unmodified protein or an analogue thereof, i.e. a protein which has been covalently modified. Typical modifications are amides, carbohydrates, alkyl groups, acyl groups, esters and the like 
     In the context of the present invention, the stratified epithelia above described is preferably epidermis, cornea, oral mucosa, etc. 
     Fibrin guarantees a solid-biological substrate to the cells allowing their growth in order to obtain a flap of genetically modified cells adhered to said substrate. 
     Fibrin is a poorly soluble fraction produced by the specific hydrolysis carried out by the thrombin of the fibrinogen alpha A chain and B beta chain to release fibrinopeptides A and B. 
     Thrombin is a protease that can act on fibrinogen to produce fibrin. In the composition of the present invention, thrombin may be present in a catalytically effective amount to convert fibrinogen into fibrin. Fibrinogen and thrombin are preferably derived from humans but may also be derived from other animals such as monkey, pig, rat, dog, bovine, etc. 
     Fibrinogen and thrombin for use in the present invention may be commercially available products. 
     Preferably, the fibrinogen and thrombin composition of the present invention also includes calcium chloride (which may be in hydrate form), aprotinin, sodium chloride. 
     An example of the composition of the present invention (for 12 ml total, i.e. 6 ml of fibrinogen mixed with 6 ml of thrombin) consists of: 
     Fibrinogen from 20 to 100 mg/ml, preferably from 20 to 50 mg/ml, more preferably from 20 to 40 mg/ml, even more preferably from 20 to 25 mg/ml; 
     Thrombin from 1 to 10 IU/ml, preferably from 3 to 8 IU/ml, more preferably from 2 to 4 IU/ml; 
     Aprotinin 1100 IU/ml to 2000 IU/ml; 
     Buffer consisting of NaCl (1-11%) and CaCl2 (1-1.5 mM). 
     Preferably, fibrin gels consist of fibrinogen (23.1 mg/ml) and thrombin (3.1 IU/ml) in NaCl (1%), CaCl 2  (1 mM) and Aprotinin (1,786 KIU/ml). 
     In a preferred form of the invention, the physiological solution (NaCl 0.9%) is used in the preparation of aprotinin. 10% NaCl is preferably used in the buffer to dissolve fibrinogen and thrombin. 
     Aprotinin and/or sodium chloride, etc., may be added to the fibrinogen before mixing the composition with the thrombin. 
     Sodium chloride can be added to the thrombin before mixing the composition with fibrinogen. Before releasing the fibrin gels, they are subjected to conformity controls as per Table 3. 
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 Features for fibrin gel releasing 
               
            
           
           
               
               
               
            
               
                   
                 Parameters 
                 Features 
               
               
                   
                   
               
               
                   
                 Transparence 
                 Opacity absence 
               
               
                   
                 Uniformity 
                 Uniform fibrin gel 
               
               
                   
                 Structural integrity 
                 Hole absence 
               
               
                   
                   
               
            
           
         
       
     
     The fibrin composition (including fibrinogen and thrombin) as described above may be used to coat a surface of the support for the preparation of cell flaps. The support may be of any type known to the art expert, provided that the cells can be cultivated on it. Support examples include untreated petri dish plates for cell cultures. Other support examples are culture plates or plates having 6 to 96 wells characterized by being able to facilitate fibrin detachment. Non-limiting examples of support material are: glass, modified glass, polystyrene, ceramic, polymethacrylate and cell culture plates, provided that the material is capable of promoting fibrin detachment. 
     The above-described composition comprising fibrinogen and thrombin can be applied to a surface of the support and left at room temperature for 10-15 minutes or until complete polymerization. The support thus obtained can be stored under sterile conditions at 4° C. 
     The term “confluence” in the context of the present invention indicates preferably the state in which the cells have such a density that there is no space among them and can be evaluated by the microscope. 
     The term “subconfluence” in the context of the present invention indicates preferably the state in which the optionally genetically modified cells, e.g. epithelial cells, have such density that are still partially surrounded by feeder cells, that state may be evaluated by the microscope. 
     Examples of genetically modified cells that can be cultivated include, but are not limited to, cardiac cells, skeletal cells, mature skeletal muscle cells, smooth muscle cells, corneal epithelial cells, epithelial cells of the oral mucosa and epidermal cells. Preferably, said cells are corneal epithelial cells, epithelial cells of the oral mucous and epidermal cells, more preferably dermal cells. The cells can be derived from humans or animals. Cells can be genetically modified and then cultured directly from the source, like an animal, or can be cultured cells of a cell line stabilized or not. 
     Cell culture can be carried out by any method or under any condition provided that the culture is conducted on the surface of the fibrin-coated support. 
     Once subconfluence is reached, the culture medium is removed and the resulting cellular flap can be washed and detached from the support using, for example, pliers. 
     Any method known to the art expert for genetic modification of cells can be used in the present invention. In a preferred aspect of the invention, the genetically modified cells described herein are characterized by the fact that exogenous nucleic acid has been introduced by the use of a viral vector, for example in the form of a viral expression construct, more preferably a Retroviral vector. Alternatively, the genetically modified cells described herein are characterized by the fact that exogenous nucleic acid is or comprises a construct of non-viral expression. 
     Preferably, in the vector as described above, the polynucleotide (or exogenous nucleic acid) is under the control of a promoter capable of expressing said polynucleotide efficiently. 
     The polynucleotide sequence in the vector is operatively linked to an appropriate expression control sequence (promoter) to direct the synthesis of the mRNA. Examples of promoters include the immediate promoter of early cytomegalovirus (CMV) genes, thymidine kinase HSV, early and late SV40, LTRs from retrovirus, preferably derived from murine leukemia virus (MLV). The vectors may also contain one or more selectable gene markers. 
     As used herein, the term “genetically modified cell” refers to a host cell that has been transduced, transformed or transfected with the polynucleotide or with the vector as described above. 
     As examples of suitable host cells, bacterial cells, fungal and yeast cells, insect cells, plant cells, animal cells, preferably human cells, and more preferably cells from biopsies of the skin, can be cited. 
     The introduction of the polynucleotide or vector previously described in the host cell may be carried out using methods known to the art expert, such as calcium phosphate transfection, DEAE-dextran mediated transfection, electroporation, lipofection, microinjection, viral infection, thermal shock, cell fusion, . . . . 
    
    
     
       The invention will be now illustrated by means of non-limiting examples referring to the following figures. 
         FIG. 1 . Representative pictures of cultured keratinocytes grown on plastic. The image on the right is representative of the flap prior to detachment and assembly for transport. 
         FIG. 2 . Representative images of the flap detachment with Dispase II and two preparations of the flap originated from plastic. The center image shows a flap not conforming to the release due to the presence of air bubbles, while the photo on the right represents the image of a flap conforming to the release. 
         FIG. 3 . Representative images of the confluences reached by growing keratinocytes on fibrin supports at the time of detachment and preparation for transport. 
         FIG. 4 . Representative images of the preparation of the genetically modified epidermis flap. 
     
    
    
     EXAMPLES 
     Materials and Methods 
     Isolation of Epidermal Keratinocytes from Biopsy of Human Skin 
     Primary human keratinocytes are isolated from 2-9 cm 2  skin biopsies after submission and adhesion to informed consent. The biopsy is subjected to enzymatic digestion in Trypsin-EDTA solution at 37° C. To obtain maximum yield and minimize the risk of toxicity from exposure to trypsin-EDTA or prolonged suspension time of keratinocytes during extraction, till 6 sequential trypsinizations of 30′ each are performed. After each trypsinization the cellular material is recovered and the trypsinizations 1-3 and 4-6 are combined and plated in plastic supports according to the cell yield at a density of 1.33×10 4  cells/cm 2  on a feeder layer of lethal irradiated murine cells 3T3-J2 (Rheinwald, J. et al. 1975). The medium used consists of a mixture of Dulbecco&#39;s modified Eagle (DMEM) and Ham F12 (2:1) supplemented with 10% fetal bovine serum, 0.5% penicillin-streptomycin, 2% glutamine, insulin (5 μg/ml), adenine (0.18 mM), hydrocortisone (0.4 μg/ml), cholera toxin (0.1 nM) and triiodothyronine (2 nM). After 3 days, this culture medium is removed and replaced with KC (KNO medium containing 10 ng/ml of EGF) which is changed every other day until the subconfluence stage is reached. 
     Primary Culture and Transduction of Keratinocytes. 
     After reaching the subconfluence (80-95%), the cells are subjected to enzymatic digestion with trypsin-EDTA for 15′ at 37° C. The cell suspension thus obtained is plated to a density of 1.33×10 4  cells/cm 2  on the feeder layer composed of 3T3J2 and AM12 cells (packaging cells) (Mavilio et al., Nature, 2006) producing the retroviral vector carrying the beta3 chain of laminin 5 (8×10 4  cells/cm 2 ) in a 1:2 ratio. After 3 days, the cells are transferred onto a new 3T3-J2 layer feeder, which is plated on a support of the same size and grown to subconfluence. Once the transduced cells have reached subconfluence, they are trypsinized as previously described. The cells thus obtained are divided into appropriate freezing vials of 1-2×10 6  cells. In parallel, process control tests are performed. Process controls consist of: 
     1. Evaluation of the number of transduced cells. A number from 1000 to 10,000 cells is plated on feeder layer in “multiwells/chambers” for the evaluation of the number of positive cells at the transgene. 
     2. Evaluation of the “colony forming efficiency” CFE. A number from 500 to 2000 cells is plated on a 100 mm dish and stained after 12 days in rhodamine. 
     3. Evaluation of the number of 3T3J2 and AM12 cells present in the cell suspension. 
     Gel Fibrin Production in 144cm 2  Supports 
     Fibrin is produced by the inventor and comprises two fibrinogen reagents (23.1 mg/ml) and thrombin (3.1 IU/ml) produced by Kedrion and sold with the commercial name Kolfib. The production process involves three phases: 
     1. Preparation of fibrinogen solution and thrombin 
     2. Preparation of fibrin support 
     3. Fibrin compliance test 
     1. A thrombin (kedrion) vial containing 625 IU or 1250 IU of thrombin is reconstituted in 10 ml of buffer consisting of NaCl (1.1%) and CaCl2 (1 mM). The entire content is then transferred to a 50 ML tube to which other 10 ML buffer will be added. If the starting vial contained 625 UI of thrombin, a 1:5 dilution of the reconstituted solution is made, e.g. 5 ML of the reconstituted solution are transferred in a new 50 ml tube and after 20 ML of buffer are added. If the starting vial contained 1250 UI of thrombin, a dilution of 1:10 of the reconstituted solution is made, e.g 18 ML of the reconstituted solution are transferred in a new 50 ML tube and other 162 ml of buffer are added. The solution is prepared at room temperature and examined to ensure that there are no solubilized thrombin solutions. A 120 mg or 240 mg fibrinogen vial is solubilized in 2.59 ML or 5.184 ML of buffer containing NaCl (1.73%) and CaCl2 (1.23 mM) and aprotinin (3574 KIU/ml). The reconstituted solution is incubated at 36.5° C. for 30 to 60 minutes to complete the solubilization. 
     2. The fibrin gel (or fibrin substrate) is prepared in a 144 cm 2  support in untreated plates for cell culture. To obtain a 100 mm thick gel, 6 ML of thrombin solution and 6 ML of fibrinogen solution are mixed to obtain a homogeneous mixture. The plates thus prepared are left at room temperature for 10-15 min until full polymerization and then stored at 4° C. for up to one month. 
     3. Before releasing the fibrin gel are subjected to compliance checks (see Table 3). 
     Flaps Preparation 
     The first step in the preparation of the genetically modified epidermis flap consists in plating 3T3-J2 feeder cells on the 144 cm 2  fibrin support. The feeder cells are plated 2 to 24 h before the keratinocyte plating or at the same time of the thawing of transduced keratinocytes. 
     The feeder cells are plated on the upper surface of the fibrin, the homogeneous plating of the feeder is controlled through an optical microscope inspection with 10× and 20× magnification. A vial of transduced cells is thawed and plated on supports previously described at a density of 500,000-3,000,000 cells transduced for a surface of 144 cm 2 . The prepared culture is transferred to an incubator at 37° C., 6% CO2 and 99% humidity, monitored and the medium is changed every two days until reaching the subconfluence (7-14 days). 
     Preparation of Flaps for Transport 
     Once the subconfluence is reached, the culture medium is removed. The genetically modified epidermis flap is washed three times with a washing and transport solution consisting of DMEM and L-Glutamine. Once the washings have been carried out, the flap is detached from the plastic container by means of sterile forceps and then transferred to the transport container for the flap to which the transport medium will be added. The container is then sealed to keep the environment sterile inside it. At this stage it will be necessary to avoid the formation of air bubbles. The fibrin flap thus prepared has a stability of 36 hours. 
     REFERENCES 
     Barrandon Y, Green H. 1987. Three clonal types of keratinocyte with different capacities for multiplication. Proc Natl Acad Sci USA 84:2302-2306. 
     Bauer J W, Koller J, Murauer E M, De Rosa L, Enzo E, Carulli S, Bondanza S, Recchia A, Muss W, Diem A, Mayr E, Schlager P, Gratz I K, Pellegrini G, De Luca M. 2017. Closure of a Large Chronic Wound through Transplantation of Gene-Corrected Epidermal Stem Cells. J Invest Dermatol 137:778-781. 
     Cuono C, Langdon R, McGuire J. 1986. Use of cultured epidermal autografts and dermal allografts as skin replacement after burn injury. Lancet 1:1123-1124. 
     De Luca M, Albanese E, Bondanza S, Megna M, Ugozzoli L, Molina F, Cancedda R, Santi P L, Bormioli M, Stella M, et al. 1989. Multicentre experience in the treatment of burns with autologous and allogenic cultured epithelium, fresh or preserved in a frozen state. Burns 15:303-309. 
     De Luca M, Pellegrini G, Green H. 2006. Regeneration of squamous epithelia from stem cells of cultured grafts. Regen Med 1:45-57. 
     Fine J D. 2010. Inherited epidermolysis bullosa: recent basic and clinical advances. Curr Opin Pediatr 22:453-458. 
     Gallico G G, 3rd, O&#39;Connor N E, Compton C C, Kehinde O, Green H. 1984. Permanent coverage of large burn wounds with autologous cultured human epithelium. N Engl J Med 311:448-451. 
     Mavilio F, Pellegrini G, Ferrari S, Di Nunzio F, Di Iorio E, Recchia A, Maruggi G, Ferrari G, Provasi E, Bonini C, Capurro S, Conti A, Magnoni C, Giannetti A, De Luca M. 2006. Correction of junctional epidermolysis bullosa by transplantation of genetically modified epidermal stem cells. Nat Med 12:1397-1402. 
     Nicholase. O&#39;Connor J M, Susan Banks-Schlegel, Olaniyi Kehinde, Howard Green. . 1981. Grafting of burns with cultured epithelium prepared from autologous epidermal cells. Lancet 1:75-78. 
     Pellegrini G, Rama P, Matuska S, Lambiase A, Bonini S, Pocobelli A, Colabelli R G, Spadea L, Fasciani R, Balestrazzi E, Vinciguerra P, Rosetta P, Tortori A, Nardi M, Gabbriellini G, Traverso C E, Macaluso C, Losi L, Percesepe A, Venturi B, Corradini F, Panaras A, Di Rocco A, Guatelli P, De Luca M. 2013. Biological parameters determining the clinical outcome of autologous cultures of limbal stem cells. Regen Med 8:553-567. 
     Pellegrini G, Ranno R, Stracuzzi G, Bondanza S, Guerra L, Zambruno G, Micali G, De Luca M. 1999. The control of epidermal stem cells (holoclones) in the treatment of massive full-thickness burns with autologous keratinocytes cultured on fibrin. Transplantation 68:868-879. 
     Rama P, Matuska S, Paganoni G, Spinelli A, De Luca M, Pellegrini G. 2010. Limbal stem-cell therapy and long-term corneal regeneration. N Engl J Med 363:147-155. 
     Rheinwald J G, Green H. 1975. Serial cultivation of strains of human epidermal keratinocytes: the formation of keratinizing colonies from single cells. Cell 6:331-343. 
     Watt F M, Jordan P W, O&#39;Neill C H. 1988. Cell shape controls terminal differentiation of human epidermal keratinocytes. Proc Natl Acad Sci USA 85:5576-5580.