Patent Abstract:
a engineered composition and method of delivery of said composition providing effective therapy for the treatment of ulcerative colitis , and crohn &# 39 ; s disease .

Detailed Description:
fxiii ( factor xiii ) is a zymogen of a class of enzymes known as transglutaminases that can form lysine crosslinks between two polypeptide chains . it has been shown that fxiii of plasma is a tetramer consisting , of two types of subunits ( a2b2 ), while in cellular fxiii only the potentially active a subunits are present . it has been noted that fxiii plays an important role in the regulation of fibrinolysis , which is a critical aspect of the blood coagulation cascade . also , the cellular form of fxiii is present in monocytes and different types of macrophages , including tissue macrophages . it has become clear that fxiii , in addition to a clotting factor , is also a cellular enzyme with implications far beyond the clotting system . this invention describes a composition and the use of a composition that is engineered to enhance the performance of fibrin stabilizers for inflammatory bowel diseases by integrating one or more ligands that bind fxiii proteins to sections of the bowel heretofore incapable of receiving said fxiii , whether naturally extracted or synthesized . we refer to this class of composition as leached ligand fibrin stabilizing ( llfs ) composition . in the thirty - three patients evaluated , 10 / 18 ( 55 . 6 %) patients under fxiii and 4 / 15 ( 26 . 7 %) under placebo achieved remission on day 42 demonstrating a clear trend towards significance . also , the median cai dropped in the subjects treated with fxiii from 12 to 6 on day 14 and further down to 2 on day 42 as compared to placebo ( 11 at start , 5 on day 14 , 6 on day 42 ). ligands are used in affinity chromatography due to absorbent ability to specifically recognize the protein of interest . when a mixture of proteins is passed through the column , only those few that bind strongly to the ligand stick , while the others pass through the column . covalent interaction occurs allowing the protein of interest to adhere to the column material . protein of interest is eluted with a buffer containing free ligand , which competes with the column ligand to bind to the protein , and protein washes off however bound or leached ligand will also pass within the solution . based on the quantitative analysis of a composite index score for ulcerative colitis it is claimed that a response to treatment in patients with the disease can be measured in as few as three to four clays or as long as 42 days . the colitis activity index ( cai ) is a quantitative measurement that incorporates a minimum of the following : in another embodiment , the material elution process is used to engineer a fibrin - stabilizing composition : since the early nineteen seventies , affinity chromatography has been investigated for its use in the purification of many biomolecules . these methods present advantages of a several thousand - fold enrichment of the target protein out of large volumes of crude starting materials , combined with high recoveries as well as the targeted separation of active and inactive material of denatured or functionally different forms . roque et at . ( roque et al ., 2007 ) and low et al . ( low et al ., 2007 ) have written reviews of the development of affinity ligands used for plasma purification . the removal of the target molecules is very efficient ; more than 95 % can easily be achieved . non - specific binding of other proteins is possible due to the low affinity effect of the ligand . to the molecule of interest . one of the main disadvantages affinity resins is ligand leaching . as much as 1 . 45 μg / ml and 1 . 76 μg / ml ligand were detected in the final container concentrated to a 10 % protein solution . fibrin stabilizing compound is in the family of serine proteases which are further classified into clans of proteases or otherwise known as a group of enzymes whose catalytic function is , to breakdown the bonds of proteins . the identified clan for fibrin stabilizing compound is classified as chymotrypsin type of amino acids that is contains a side - chain molecule specific to each . these proteases are directly involved in chemical reactions or catalysis . they function as a general acid - base , electrophilic or nucleophilic catalysts and polarize and stabilize the transition state of binding interactions . however the facilitated catalysis reaction remains a mystery . serine proteases are probably the most thoroughly investigated enzyme system . catalysis and specificity are not simply controlled by a few residues , but are rather a property of the entire protein framework , controlled via the distribution of charge across a network of hydrogen bonds and perhaps also by the coupling of domain motion to the chemical transformation . fibrinogen , factor v factor viii and factor xiii ( fxiiii ) contain neutral or positively charged residues that influence binding specificity . this binding capability allows for other like molecules to potentially form linkages . in a preferred embodiment , rats were pre - dosed with 20 mg / kg tnbs to induce ulcerative colitis . once induced , rats were treated with either vehicle control or fxiii . rats showed a dose response for fxiii levels in serum . 80 u / kg group showed statistically significant improvement in histological colon scores from vehicle control at 10 days . 40 u / kg group showed a trend towards significance for the same parameter . there was also an indication of re - epithelialization ( healing ) in two treated ( one at 80 u / kg and one at 160 u / kg ) rats . these results confirm that moderate to severe ulcerative colitis in animals is accompanied by an acquired deficiency of plasma fxiii . further , this acquired deficiency is mechanistically relevant to the disease state . finally , therapeutic replacement of plasma fxiii results in amelioration of the disease that can be measured quantitatively through the microscopic evaluation of mucosal tissue in the colon . all numerical ranges herein include all numerical values and ranges of all numerical values within the recited numerical ranges . notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations , the numerical values set forth in the specific examples are reported as precisely as possible . any numerical value , however , inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements . the references cited throughout this application , are incorporated for all purposes apparent herein and in the references themselves as if each reference was fully set forth . for the sake of presentation , specific ones of these references are cited at particular locations herein . a citation of a reference at a particular location indicates a manner in which the teachings of the reference are incorporated . however , a citation of a reference at a particular location does not limit the manner in which all of the teachings of the cited reference are incorporated for all purposes . it is understood , therefore , that this invention is not limited to the particular embodiments disclosed , but is intended to cover all modifications which are within the spirit and scope of the invention as defined by the appended claims ; the above description ; and / or shown in the exhibit ( page 5 ). buchacher , a . & amp ; iberer , g . 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