Patent Application: US-75276096-A

Abstract:
a chimeric adenoviral vector is provided that comprises nucleotide sequence of a first adenovirus , wherein at least one gene of said first adenovirus encoding a protein that facilitates binding of said vector to a target mammalian cell , or internalization thereof within said cell , is replaced by the corresponding gene from a second adenovirus belonging to subgroup d , said vector further comprising a transgene operably linked to a eucaryotic promoter to allow for expression therefrom in a mammalian cell . additionally , a method of delivering transgenes to target mammalian cells , particularly airway epithelial cells , is provided .

Description:
a detailed discussion of adenovirus is found in m . s . horwitz , &# 34 ; adenoviridae and their replication &# 34 ;, and &# 34 ; adenoviruses &# 34 ;, chapters 60 and 61 , respectively , in virology b . n . fields et al ., eds ., 2nd edition , raven press , ltd ., new york , 1990 , and reference therein is found to numerous aspects of adenovirus pathology , epidemiology , structure , replication , genetics and classification . briefly , the human adenoviruses ( ads ) are divided into numerous serotypes ( approximately 47 , classified into 6 subgroups a , b , c , d , e and f ), based upon properties including hemagglutination of red blood cells , oncogenicity , dna base and protein amino acid compositions and homologies , and antigentic relationships ( see for example m . s . horwitz , above , at pages 1684 - 1685 ). additional background information concerning ad classification including for subgroup d can be found , for example , in f . deryckere et al ., journal of virology , 70 , 1996 , pp . 2832 - 2841 ; and a . bailey et al ., virology , 205 , 1994 , pp . 438 - 452 , and in other art - recognized references . as recited by m . s . horwitz , adenoviruses are nonenveloped , regular icosahedrons ( having 20 triangular surfaces and 12 vertices ) that are about 65 - 80 nm in diameter . a protein called &# 34 ; fiber &# 34 ; projects from each of these vertices . the fiber protein is itself generally composed of 3 identical polypeptide chains , although the length thereof varies between serotypes . the protein coat ( capsid ) is composed of 252 subunits ( capsomeres ), of which 240 are &# 34 ; hexons &# 34 ;, and 12 are &# 34 ; pentons &# 34 ;. each of the pentons itself comprises a penton base , on the surface of the capsid , and a fiber protein projecting from the base . the ad 2 penton base protein has been determined to be a 8 × 9 nm ring shaped complex composed of 5 identical protein subunits of 571 amino acids each . additional background information may be found in u . s . pat . no . 5 , 559 , 099 and references cited therein . in general , it appears that adenovirus utilizes two cellular receptors to attach to , and then infect a target cell . it has been suggested that the fiber protein of an infecting adenovirus first attaches to a receptor , the identify of which is still unknown , and then penton base attaches to a further receptor , often a protein of the alpha integrin family . a review of this aspect of the art may be found , for example , in aforementioned u . s . pat . no . 5 , 559 , 099 . it has been determined that alpha - integrins often recognize short amino acid sequences on other cellular proteins for attachment purposes including the tripeptide sequence arg - gly - asp ( abbreviated rgd ). an rgd sequence is found in penton base protein of adenovirus and is understood in the art to mediate attachment of ad to alpha integrins . the present invention involves the recognition that adenoviral vectors that are either based substantially upon the genome of ad serotypes classified in subgroup d , or that contain certain ad - protein encoding polynucleotide sequences of subgroup d adenovirus , are particularly effective at binding to , and internalizing within , human cells , such that therapeutic transgenes included in the adenoviral vector are efficiently expressed . in a particularly important aspect of the invention , it has been determined that adenovirus serotypes within subgroup d are particularly effective to bind to and internalize within epithelial cells of the human respiratory system . this discovery is particularly surprising given that adenovirus serotypes of subgroup d are not clinically associated with human respiratory disease , and that , for example association with conjunctivitis is more typical . the recognition of this tropism is of particular importance for the treatment by gene therapy of recognized disease states of the lung such as cystic fibrosis or alpha 1 - antitrypsin deficiency . according to the practice of the invention , it is preferred that an adenovirus vector utilized to deliver a therapeutic transgene to the respiratory epithelium ( including of the nasal airway , trachea , and bronchi and alveoli of the lung ), or to other tissues of the body , be selected from the serotypes within subgroup d , as such classification is recognized in the art . preferred serotypes include those selected from ad 9 , ad 15 , ad 17 , ad 19 , ad 20 , ad 22 , ad 26 , ad 27 , ad 28 , ad 30 , and ad 39 , although use of other , and potentially less effective , serotypes within subgroup d still provides a substantial improvement in the state of the art . a particularly effective adenoviral vector is that based upon the genome of ad 17 . in connection with the design of adenoviral vectors based on the subgroup d viruses , reference may be made to the substantial body of literature on how such vectors may be designed , constructed and propagated , including for example , international patent publication wo 94 / 12649 , wherein deletion of the el region , partial or complete deletion of the e4 region , and deletions within , for example , the e2 and e3 regions have been described . of particular importance in the provision of such vectors is the existence of a complimenting cell line in which the vector can be maintained , for example , by analogy with the use of 293 cells to propagate ad 2 . an important consideration in the generation of such cell lines is the provision by the host cells in trans of certain viral functions , that are desireably deleted from the vector , including , for example the e1a and e1b functions of adenovirus . that such cell lines can be readily generated according to the standard of the current art is evidenced by l . e . babiss et al ., journal of virology , 46 , 1983 , pp . 454 - 465 . in this regard , the use of her3 cells ( human embryonic retinoblasts transformed by ad 12 ), as a a complimenting cell line is of note . additionally , there is substantial evidence that any reported transforming properties of the e4 region of certain subgroup d serotypes do not extend to ad serotypes whose use is preferred according to the practice of the present invention ( see , for example , r . javier et al ., science , 257 , 1992 , pp . 1267 - 1271 ). it is expected also that , for example , individual orfs of the subgroup d e4 region , such as orf1 , could be deleted . in an additional preferred aspect of the invention , the gene encoding a fiber , a penton base , or the genes for each , or for a subdomain of either or both , and derived from a serotype of subgroup d , is used in replacement for the corresponding encoding sequence from the starting ad vector backbone . for the purposes of this example , &# 34 ; gene &# 34 ; means any nucleotide sequence , whether a gene , or a cdna , and the like , that can be successfully used to express the protein product . example 1 infection of nhbe cells by adenovirus serotypes of subgroup d normal human bronchial epithelial (&# 34 ; nhbe &# 34 ;) cells were obtained from clonetics ( san diego , calif . ), and plated on costar ( cambridge , mass .) transwell - clear polyester membranes that were pre - coated with human placental collagen . the wells were placed in a cluster plate and cells were fed every day for one week by changing the medium in both the well and the plate . after one week the media was removed from the wells to create an air - liquid interface , and the cells were then fed only by changing the medium in the cluster plate , every other day for one week . cells were infected at an moi of 1 by adding virus ( see below ) to the transwell , followed by an incubation time of 1 . 5 - 2 hours . at the end of the incubation period , the medium was removed and the cells were gently rinsed with fresh medium . thirty - six hours post - infection the cells were fixed with 1 : 1 acetone : methanol , permeablized with a solution of 0 . 05 % tween 20 in pbs , and stained with fitc labeled anti - hexon antibody ( chemicon , temecula , calif .) to visualize cells that had been productively infected ( i . e . to visualize virus replication ). cells were also subjected to the dapi staining procedure in order to visualize the total number of nuclei . the results could be readily determined upon simple inspection . wild type ad serotypes within subgroup d that were tested included 9 , 15 , 17 , 19 , 20 , 22 , 26 , 27 , 28 , 30 , and 39 ( all from the american type culture collection , rockville , md .). an ad 2 ( obtained as dna from brl , gaithersburg , md ., and used to transfect 293 cells in order to generate virus stock ) was used as a control . infection observed with all of the subgroup d serotypes was superior to that observed with ad2 , with the best results being achieved with ad 9 , ad 17 , ad 20 , ad 22 , and ad 30 . additionally , it was determined under similar circumstances that each of the above - mentioned serotypes of subgroup d was more effective in the nhbe cell assay than any other serotype tested than belongs to a subgroup other than d . in this regard , the following serotypes were tested : 31 ( subgroup a ); 3 ( subgroup b ); 7 ( subgroup b ); 7a ( subgroup b ); 14 ( subgroup b ); 4 ( subgroup e ); and 41 ( subgroup f ). in a further experiment , serotype 35 ( subgroup a ) may have performed as well as the least effective members of subgroup d that were tested . following generally the procedures of example 1 , human bronchial epithelial cells recovered from healthy human volunteers were infected with either ad 2 ( as above , ad2 dna was obtained from brl , and this dna was used to transfect 293 cells to generate virus ) ( fig1 ), or ad 17 ( from atcc ) ( fig2 ), all at an moi of 50 . cells were left in contact with virus for 30 minutes , 3 hours , or 12 hours . the increased tropism of ad 17 for human bronchial epithelial cells , compared with ad 2 , is readily apparent upon inspection of fig1 and 2 . in the figures , the right hand columns ( panels d , e , and f ,. stained in blue ) show total numbers of cells present ( from dapi staining as above ), whereas the left hand columns ( panels a , b , and c , stained in green ) quantify adenovirus hexon protein present in the infected cells ( from fitc - labeled anti - hexon antibody , as above ). panels a and d result from 30 minute incubation times , panels b and e result from 3 hour incubation times , and panels c and f result from 12 hour incubation times . as measured by the technique employed , infection of airway epithelia by ad17 is at least 50 fold greater than by ad 2 for the thirty minute incubation time . example 3 binding of ad 2 and ad17 to human nasal polyp cell isolates 293 cells , a complementing cell line developed by graham et al . ( see gen . virol . , 36 , 1977 , pp . 59 - 72 ), were infected with either wild type ad2 or wild type ad17 . five hours post - infection the media was removed and replaced with methionine free media containing s 35 metabolic label ( amersham ). after an additional six hours , fresh media was added and the labeling was allowed to proceed for a total of 18 hours , after which the s 35 media was removed and replaced with fresh media . thirty hours post - infection the cells were harvested and lysed and the labeled ad2 or ad 17 viruses were purified by cscl gradient centrifugation . the recovered viruses were then used in an assay to determine their relative binding efficiency on human nasal polyp cells . in order to perform the assay , ciliated human airway epitehlial cells were recovered from nasal polyps of healthy volunteers . the results from two such isolates , np - 14 and np - 15 , are reported here ( see fig3 ). radiolabeled virus was then incubated with the isolated cells in wells for specified times ( 5 or 30 minutes , see fig3 ). the cells were then rinsed and measured for radioactivity . binding as reported in fig3 indicates the percent of input radioactivity that is cell associated . it was determined that for both cell isolate populations , using either 5 or 30 minute incubations , cell associated radioactivity was 10 - fold enhanced if ad 17 rather than ad 2 was used . a549 cells ( a human lung carcinoma line , obtained from the american type culture collection as atcc ccl - 185 ) were plated at 3 × 10 4 cells per well in 96 - well dishes . since the number of receptor sites for adenovirus fiber on the cell surface has been estimated to be approximately 10 5 receptors per cell , the receptors in the plated cells were saturated , in this example , with 0 . 1 μg of purified full length ad 2 fiber protein ( obtained from paul freimuth , brookhaven national laboratory , upton , n . y . ), which corresponds to approximately 100 molecules of fiber per receptor . cells were incubated with ad 2 fiber in pbs for two hours at 37 ° c . the cells were subsequently infected at an moi of 1 ( using either ad2 provided as above , or wild type ad 17 ) for one hour , after which the cells were rinsed , and fresh medium was added . control cultures were incubated with pbs with no added protein for two hours and then subsequently infected as described above . forty hours post - infection the cells were fixed with 1 : 1 acetone : methanol , permeablized with 0 . 05 % tween 20 in pbs and stained with fitc labeled anti - ad2 hexon antibody , as described in example 1 . as determined by this assay , the number of cells infected ( stained ) with ad2 was reduced by approximately 90 % in cultures that were pre - incubated with ad2 fiber as compared to control cultures . however , no effect on ad17 infection was observed by the pre - incubation of a549 cells with full length ad2 fiber . example 5 use of ad 2 fiber knob in a binding competition experiment with ad 2 further competition experiments were performed with ad2 and ad17 fiber knobs that had been expressed and purified from e . coli . dna sequences encoding both protein fragments were designed so that the fiber knobs expressed therefrom would contain histidine tags in order to permit nickel - column purification . the yield of soluble fiber knob trimer , purified by the ni - nta method ( qiagen , chatsworth , calif . ), was ˜ 25μg / 50 ml culture . a significant portion of the total knob protein expressed appeared to remain in a monomeric ( and insoluble ) form . the soluble trimeric material obtained was used for a preliminary competition experiment . wild type ad2 and ad17 were used to infect a549 cells , or cells that had been pre - incubated with excess ( about 100 molecules of trimer per receptor ) ad2 fiber knob or ad17 fiber knob . the results indicated that ad2 fiber knob , but not ad17 knob , could block ad 2 infection . additionally , ad 17 infection was not blocked by e . coli - expressed fiber knobs of either serotype , suggesting that the mechanism of ad 2 and ad 17 infections is different . the vector ad2 / βgal - 2 was constructed as follows . a cmvβgal expression cassette was constructed in a pbr322 - based plasmid that contained ad2 nucleotides 1 - 10 , 680 from which nucleotides 357 - 3328 were deleted . the deleted sequences were replaced with ( reading from 5 &# 39 ; to 3 &# 39 ;): a cytomegalovirus immediate early promoter ( obtained from prc / cmv , invitrogen ), lacz gene encoding β - galactosidase with a nuclear localization signal , and an sv40 polyadenylation signal ( nucleotides 2533 - 2729 ). the resulting plasmid was used to generate ad2 / βgal - 2 by recombination with ad2e4orf6 ( d . armentano et al ., human gene therapy , 6 , 1995 , pp 1343 - 1353 ). a chimeric ad2 / βgal - 2 / fiber ad17 viral vector ( fig4 ) was then constructed as follows . padorf6 ( d . armentano et al ., human gene therapy 6 , 1995 , pp 1343 - 1353 was cut with nde and bamhi to remove ad2 fiber coding and polyadenylation signal sequences ( nucleotides 20624 - 32815 ). an ndei - bamhi fragment containing ad17 fiber coding sequence ( nucleotides 30835 - 32035 ) was generated by pcr and ligated along with an sv40 polyadenylation signal into ndei - bamhi cut padorf6 to generate padorf6fiber17 . this plasmid was cut with pacd and then ligated to paci - cut ad2 / βgal - 2 dna to generate ad2 / βgal - 2fiber 17 . a therapeutic transgene may be substituted in this construct for the reporter gene . a similar construct can be prepared using a dna sequence that encodes ad 17 penton base instead of ad 17 fiber . alternatively only a subregion of the penton base of ad 2 need be subject to replacement , such as by inserting into the vector a nucleotide encoding sequence corresponding to any amino acid subsequence of ad 17 penton base amino acids 283 - 348 in replacement for any subsequence of ad 2 penton base amino acids 290 - 403 . preferably , the replaced sequence of ad 2 and the inserted sequence of ad 17 includes the rgd domain of each . use of nucleotide sequence corresponding to penton base amino acid sequence for other subgroup d serotypes is also within the practice of the invention . __________________________________________________________________________sequence listing ( 1 ) general information :( iii ) number of sequences : 3 ( 2 ) information for seq id no : 1 :( i ) sequence characteristics :( a ) length : 35081 base pairs ( b ) type : nucleic acid ( c ) strandedness : single ( d ) topology : linear ( xi ) sequence description : seq id no : 1 : catcatcaataatataccccacaaagtaaacaaaagttaatatgcaaatgaggttttaaa60tttagggcggggctactgctgattggccgagaaacgttgatgcaaatgacgtcacgacgc120acggctaacggtcgccgcggaggcgtgwctagcccggaagcaagtcgcggggctgatgac180gtataaaaaagcggactttaaacccggaaacggccgattttcccgcggccacgcccggat240atgaggtaattctgggcggatgcaagtgaaattaggtcattttggcgcgaaaactgaatg300aggaagtgaaaagtgaaaaataccggtcccgcccagggcggaatatttaccgagggccga360gagactttgaccgattacgtgtgggtttcgattgcggtgttttttcgcgaatttccgcgt420ccgtgtcaaagtcccgtgtttatgtcacagatcagctgatccacagggtatttaaaccag480tcgagcccgtcaagaggccactcttgagtgccagcgagtagagatttctctgagctccgc540tcccagagtgtgagaaaaatgagacacctgcgcctcctgcctggaactgtgcccttggac600atggccgcattattgctggatgactttgtgagtacagtattggaggatgaactgcaacca660actccgttcgagctgggacccacacttcaggacctctatgatttggaggtagatgcccag720gaggacgacccgaacgaagatgctgtgaatttaatatttccagaatctctgattcttcag780gctgacatagccagcgaagctctacctactccacttcatactccaactctgtcacccata840cctgaattggaagaggaggacgagttagacctccggtgttatgaggaaggttttcctccc900agcgattcagaggacgaacagggtgagcagagcatggctctaatctcagactatgcttgt960gtggttgtggaagagcattttgtgttggacaatcctgaggtgcccgggcaaggctgtaaa1020tcctgccagtaccaccgggataagaccggagacacgaacgcctcctgtgctctgtgttac1080atgaaaaagaacttcagctttatttacagtaagtggagtgaatgtgagagaggctgagtg1140cttaagacataactgggtgatgcttcaacagctgtgctaagtgtggtttattttgtttct1200aggtccggtgtcagaggatggtcatcaccctcagaagaagaccacccgtgtccccctgat1260ctgtcaggcgaaacgcccctgcaagtgcacagacccaccccagtcagacccagtggcgag1320aggcgagcagctgttgaaaaaattgaggacttgttacatgacatgggtggggatgaacct1380ttggacctgagcttgaaacgtcccaggaaactaggcgcagctgcgcttagtcatgtgtaa1440ataaagttgtacaataaaaattatatgtgacgcatgcaaggtgtggtttatgactcatgg1500gcggggcttagttctatataagtggcaacacctgggcactggagcacagaccttcaggga1560gttcctgatggatgtgtggactatccttgcagactttagcaagacacgccggcttgtaga1620ggatagttcagacgggtgctccgggttctggagacactggtttggaactcctctatctcg1680cctggtgtacacagttaaaaaggattataacgaggaatttgaaaatctttttgctgattg1740ctctggcctgctagattctctgaatctcggccaccagtcccttttccaggaaagggtact1800ccacagccttgatttttccagcccagggcgcactacagccggggttgcttttgtggtttt1860tctggttgacaaatggagccagaacacccaactgagcaggggctacattctggacttcgc1920agccatgcacctgtggagggcatgggtcaggcagcggggacagagaatcttgaactactg1980gcttctacagccagcagctccgggtcttcttcgtctacacagacaaacatccatgttgga2040ggaagaaatgaggcaggccatggacgagaacccgaggagcggtctggaccctccgtcgga2100agaggagttggattgaatcaggtatccagcctgtacccagagcttagcaaggtgctgaca2160tccatggccaggggagtgaagagggagaggagcgatgggggcaataccgggatgatgacc2220gagctgacggccagtctgatgaatcgcaagcgcccagagcgccttacctggtacgagcta2280cagcaggagtgcagggatgagttgggcctgatgcaggataaatatggcctggagcagata2340aaaacccattggttgaacccagatgaggattgggaggaggctattaagaagtatgccaag2400atagccctgcgcccagattgcaagtacatagtgaccaagaccgtgaatatcagacatcct2460gctacatctcggggaacggggcagaggtggtcattgataccctggacaaggccgccttta2520ggtgttgcatgatgggaatgagagccggagtgatgaatatgaattccatgatctttatga2580acatgaagttcaatggagagaagtttaatggggtgctgttcatggccaacagccacatga2640ccctgcatggctgcgactttttcggctttaacaatatgtgcgcagaggtctggggcgctt2700ccaagatcaggggatgtaagttttatggctgctggatgggcgtggtcggaagacccaaga2760gcgagatgtctgtgaagcagtgtgtgtttgagaaatgctacctgggagtctctaccgagg2820gcaatgctagagtgaggcactgctcttccctggagacgggctgcttctgcctggtgaagg2880gcacagcctctctgaagcataatatggtgaagggctgcacggatgagcgcatgtacaaca2940tgctgactgcgactcgggggtctgtcatatcctgaagaacatccatgtgacctcccaccc3000cagaaagaagtggccagtgtttgagaataacatgctgatcaagtgccacatgcacctggg3060cgccagaaggggcaccttccagccgtaccagtgcaactttagccagaccaagctgctgtt3120ggagaacgatgccttctccagggtgaacctgaacggcatctttgacatggatgtctcggt3180gtacaagatcctgagatacgatgagaccaagtccagggtgcgcgcttgcgagtgcggggg3240cagacacaccaggatccagccagtggccctggatgtgaccgaggagctgagaccagacca3300cctggtgatggcctgtaccgggaccgagttcagctccagtggggaggacacagattagag3360gtaggtttgagtagtgggcgtggctaaggtgactataaaggcgggtgtcttacgagggtc3420tttttgcttttctgcagacatcatgaacgggaccggcggggccttcgaaggggggctttt3480tagcccttatttgacaacccgcctgccaggatgggccggagttcgtcagaatgtgatggg3540atcgacggtggacgggcgcccagtgcttccagcaaattcctcgaccatgacctacgcgac3600cgtggggaactcgtcgcttgacagcaccgccgcagccgcggcagccgcagccgccatgac3660agcgacgagactggcctcgagctacatgcccagcagcagcagtagcccctctgtgcccag3720ttccatcatcgccgaggagaactgctggccctgctggccgagctggaagccctgagccgc3780cagctggccgccctgacccagcaggtgtccgagctccgcgaacagcagcagcaaaataaa3840tgattcaataaacacatattctgattcaaacagcaaagcatctttattatttattttttc3900gcgcgcggtaggccctggtccacctctcccgatcattgagagtgcggtggattttttcca3960agacccggtagaggtgggattggatgttgaggtacatgggcatgagcccgtcccgggggt4020ggaggtagcaccactgcatggcctcgtgctcggwtcgtgttgtagatgatccagtcatag4080caggggcgcgggcgtggtgctggatgatgtccttgaggaggagactgatggccacgggga4140gccccttggtgtaggtgttggcaaagcggttgagctgggagggatgcatgcggggggaga4200tgatgtgcagtttggcctggatcttgaggttggcgatgttgccacccagatcccgccggg4260ggttcatgttgtgcaggaccaccaggacggtgtagcccgtgcacttggggaacttatcat4320gcaacttggaagggaatgcgtggaagaatttggagacgcccttgtgcccgcccaggtttt4380ccatgcactcatccatgatgatggcgatgggcccgtgggctgcggctttggcaaagacgt4440ttctggggtcagagacatcataattatgctcctgggtgagatcatcataagacattttaa4500tgaattttgggcggagggtgccagattgggggacgatggtttccctcgggccccggggcg4560aagttcccctcgcagatctgcatctcccaggctttcatctcggagggggggatcatgtcc4620acctgcggggcgatgaaaaaaacggtttccggggcgggggtgatgagctgcgaggagagc4680aggtttctcaacagctgggacttgc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( 2 ) information for seq id no : 2 :( i ) sequence characteristics :( a ) length : 1101 base pairs ( b ) type : nucleic acid ( c ) strandedness : single ( d ) topology : linear ( xi ) sequence description : seq id no : 2 : atgtcaaagaggctccgggtggaagatgacttcaaccccgtctacccctatggctacgcg60cggaatcagaatatccccttcctcactcccccctttgtctcctccgatggattcaaaaac120ttcccccctggggtcctgtcactcaaactggctgacccaatcaccatagccaatggtgat180gtctcactcaaggtgggagggggacttactttgcaagaaggaagtctgactgtagaccct240aaggctcccttgcaacttgcaaacaataaaaaacttgagcttgtttatgttgatccattt300gaggttagtgccaataaacttagtttaaaagtaggacatggattaaaaatattagatgac360aaaagtgctggagggttgaaagatttaattggcaaacttgtggttttaacagggaaagga420ataggcactgaaaatttgcaaaatacagatggtagcagcagaggaattggtataagtgta480agagcaagagaagggttaacatttgacaatgatggatactrggtagcatggaacccaaag540tatgacacgcgcacactttggacaacaccagacacatctcctaattgcaggattgataag600gagaaggattcaaaactcactttggtacttacaaagtgtggaagtcaaatattagctaat660gtgtctttgattgtggtgtcaggaaaatatcaatacatagaccacgctacaaatccaact720cttaaatcatttaaaataaaacttctttttgataataaaggtgtacttctcccaagttca780aaccttgattccacatattggaactttagaagtgacaatttaactgtatctgaggcatat840aaaaatgcagttgaatttatgcctaatttggtagcctacccaaaacctaccactggctct900aaaaaatatgcaagggatatagtctatgggaacatatatcttggaggtttggcatatcag960ccagttgtaattaaggttacttttaatgaagaagcagatagtgcttactctataacattt1020gaatttgtatggaataaagaatatgccagggttgaatttgaaaccacttcctttaccttc1080tcctatattgcccaacaataa1101 ( 2 ) information for seq id no : 3 :( i ) sequence characteristics :( a ) length : 1552 base pairs ( b ) type : nucleic acid ( c ) strandedness : single ( d ) topology : linear ( xi ) sequence description : seq id no : 3 : atgaggcgtgcggtggtgtcttcctctcctcctccctcgtacgagagcgtgatggcgcag60gcgaccctggaggttccgtttgtgcctccgcggtatatggctcctacggagggcagaaac120agcattcgttactcggagctggctccgttgtacgacaccactcgcgtgtacttggtgaca180acaagtcggcggacatcgcttccctgaactatcaaaacgaccacagcaacttcctgacca240cggtggtgcagaacaacgatttcacccccgccgaggctagcacgcagacgataaattttg300acgagcggtcgcggtggggcggtgatctgaagaccattctgcacaccaacatgcccaatg360tgaacgagtacatgttcaccagcaagtttaaggcgcgggtgatggtggctagaaaacacc420cacagggggtagaagcaacagatttaagcaaggatatcttagagtatgagtggtttgagt480ttaccctgcccgagggcaacttttccgagaccatgaccatagacctgatgaacaacgcca540tcttggaaaactacttgcaagtggggcggcaaaatggcgtgctggagagcgatattggag600tcaagtttgacagcagaaatttcaagctgggctgggaccctgtgaccaagctggtgatgc660caggggtctacacctacgaggcctttcacccggacgtggtgctgctgccgggctgcgggg720tggacttcacagagagccgcctgagcaacctcctgggcattcgcaagaagcaacctttcc780aagagggcttcagaatcatgtatgaggatctagaagggggcaacatccccgccctgctgg840atgtgcccaagtacttggaaagcaagaagaagttagaggaggcattggagaatgctgcta900aagctaatggtcctgcaagaggagacagtagcgtctcaagagaggttgaaaaggcagctg960aaaaagaacttgttattgagcccatcaagcaagatgataccaagagaagttacaacctca1020tcgagggaaccatggacacgctgtaccgcagctggtacctgtcctatacctaccgggacc1080ctgagaacggggtgcagtcgtggacgctgctcaccaccccggacgtcacctgcggcgcgg1140agcaagtctactggtcgctgccggacctcatgcaagaccccgtcaccttccgttctaccc1200agcaagtcagcaactaccccgtggtcggcgccgagctcatgcccttccgcgccaagagct1260ttacaacgacctcgccgtctactcccagctcatccgcagctacacctccctcacccacgt1320cttcaaccgcttccccgacaaccagatcctctgccgtccgcccgcgcccaccatcaccac1380cgtcagtgaaaacgtgcctgctctcacagatcacgggacgctaccgctgcgcagcagtat1440ccgcggagtccagcgagtgaccgtcactgacgcccgtcgccgcacctgtccctacgtcta1500caaggccctgggcatagtcgcgccgcgtgtgctttccagtcgcaccttctaa1552__________________________________________________________________________