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Patent Issued for Acellular Tissue Matrices Made from .Alpha.-1,3-Galactose-Deficient Tissue

August 26, 2014



By a News Reporter-Staff News Editor at Life Science Weekly -- A patent by the inventors McQuillan, David J. (Doylestown, PA); Griffey, Edward S. (Fair Oaks Ranch, TX); Beniker, Herbert Daniel (San Antonio, TX); Xu, Hui (Plainsboro, NJ), filed on November 16, 2012, was published online on August 12, 2014, according to news reporting originating from Alexandria, Virginia, by NewsRx correspondents (see also LifeCell Corporation).

Patent number 8802920 is assigned to LifeCell Corporation (Branchburg, NJ).

The following quote was obtained by the news editors from the background information supplied by the inventors: "A major problem of xenotransplantation in recipient animals (e.g., humans) that do not express the enzyme UDP-galactose: .beta.-D-galactosyl-1,4-N-acetyl-D-glucosaminide .alpha.-1,3 galactosyl-transferase (.alpha.-1,3 galactosyltransferase; '.alpha.GT') that catalyzes the formation of the terminal disaccharide structure, galactose .alpha.-1,3 galactose ('.alpha.gal'), is the hyperacute rejection of xenografts in such recipients that is largely, if not exclusively, due to the action of antibodies specific for the .alpha.gal epitope on the surface of cells in the xenograft. Transgenic animals (e.g., pigs) have been derived which lack, or substantially lack, functional .alpha.GT and thus also lack, or substantially lack, .alpha.gal epitopes."

In addition to the background information obtained for this patent, NewsRx journalists also obtained the inventors' summary information for this patent: "The invention is based in part on the discovery that acellular dermal matrices (ADM) made from transgenic pigs in which both alleles of the gene encoding .alpha.GT have been disrupted such that the pigs lack the predominant .alpha.GT activity (and thus .alpha.gal epitopes on the surface of cells and on proteins of the extracellular matrix) did not stimulate the production of .alpha.gal-specific antibodies and were not infiltrated by inflammatory cells subsequent to implantation in Old World primates. The invention thus provides acellular tissue matrices made from animals (e.g., pigs) genetically modified so as to lack, or substantially lack, .alpha.gal epitopes and methods of making and using such matrices. Appropriate genetically modified animals will preferably be .alpha.GT gene-disrupted animals, i.e., animals in which both alleles of the .alpha.GT gene have been disrupted in all cells of the animal. For convenience, .alpha.GT gene-disrupted animals are referred to herein as 'GT.delta.' animals and animals that naturally lack functional .alpha.GT protein are referred to as 'GT-' animals. Animals that naturally express functional .alpha.GT protein are sometimes referred to as 'GT+' animals.

"More specifically, the invention features an acellular tissue matrix that includes: a decellularized collagen-containing tissue, or a decellularized collagen-containing organ, of an animal genetically modified such that tissues in the animal lack, or substantially lack, galactose .alpha.-1,3-galactose epitopes. The acellular tissue matrix preferably lacks, or substantially lacks, epithelial basement membrane. The animal can be, for example, a pig. The tissue or organ can include, for example, dermis, fascia, pericardium, dura, umbilical cord, placenta, cardiac valve, ligament, tendon, artery, vein, neural connective tissue, intestine, bladder, or ureter. The acellular tissue matrix can be in non-particulate or in particulate form. The genetic modification can include a disruption of both alleles of an .alpha.-1,3 galactosyl transferase (.alpha.GT) gene.

"Also embodied by the invention is a method of making an acellular tissue matrix. The method includes: (a) providing a collagen-containing tissue or a collagen-containing organ from an animal genetically modified so that tissues in the animal lack, or substantially lack, galactose .alpha.-1,3-galactose epitopes; and (b) processing the tissue or organ to so as to render the tissue or organ acellular and lacking, or substantially lacking, in epithelial basement membrane, the processing resulting in the production of an acellular tissue matrix. The animal can be a pig and the tissue or organ can any of the above-recited tissues or organs. The genetic modification can include a disruption of both alleles of an .alpha.-1,3 galactosyl transferase (.alpha.GT) gene. The method can further include freezing and/or freeze-drying the acellular tissue matrix. Moreover, the method can further include: (a) pulverizing the acellular tissue matrix; or (b) rendering the acellular tissue matrix particulate in form. The processing can include removing and discarding an epithelium (e.g., epidermis).

"Another aspect of the invention is a method of treatment. The method includes: (a) identifying a mammalian subject as having an organ, or tissue, in need of repair or amelioration; and (b) placing a composition comprising the above-described acellular tissue matrix in or on the organ or tissue. The subject can be, e.g., a human and the animal can be, e.g., a pig. The tissue or organ can be any of those recited above and the acellular tissue matrix can be non-particulate or particulate in form. The genetic modification can include disruption of both alleles of an .alpha.-1,3 galactosyl transferase (.alpha.GT) gene. The method can further comprise administration to the subject of one or more agents, e.g., a cell growth factor, an angiogenic factor, a differentiation factor, a cytokine, a hormone, or a chemokine. The one or more agents can be in the composition placed in the subject or they can be injected or infused into the subject separately from the composition. The organ or tissue of the subject can be, without limitation, skin, bone, cartilage, meniscus, dermis, myocardium, periosteum, artery, vein, stomach, small intestine, large intestine, diaphragm, tendon, ligament, neural tissue, striated muscle, smooth muscle, bladder, urethra, ureter, gingival, or fascia (e.g., abdominal wall fascia). The composition can further include demineralized bone powder. The gingiva can be, or can be proximal to, receding gingival. Moreover, the gingiva can contain a dental extraction socket.

"As used herein, the term 'placing' a composition includes, without limitation, setting, injecting, infusing, pouring, packing, layering, spraying, and encasing the composition. In addition, placing 'on' a recipient tissue or organ means placing in a touching relationship with the recipient tissue or organ.

"As used herein, a 'genetically modified' animal is an animal whose genome contains an artificially inserted exogenous nucleic acid sequence or whose genome is artificially manipulated so as to lack a wild-type nucleic acid sequence. Thus, a genetically modified animal is not one in which an exogenous sequence in its genome or the absence of a wild-type nucleic acid sequence from its genome is derived by only a breeding program as is used in, for example, the generation of congenic animal strains. In addition, a genetically modified animal is not one into whose genome a wild-type viral nucleic acid sequence has integrated in the course of a viral infection. Genetically modified animals include the progeny of the manipulated animal who carry the modification in their genomes.

"As used herein, the tissues in 'an animal that is genetically modified such that the tissues in the animal substantially lack .alpha.gal epitopes' contain less than 5% (e.g., less than: 4%; 2%; 1%; 0.1%; 0.01%; 0.001%; or even less than 0.001%) of the .alpha.gal epitopes that corresponding tissues in a corresponding wild-type animal contain.

"As used herein, the term 'operably linked' means incorporated into a genetic construct so that expression control sequences (i.e., transcriptional and translational regulatory elements) effectively control expression of a coding sequence of interest. Transcriptional and translational regulatory elements include but are not limited to inducible and non-inducible promoters, enhancers, operators and other elements that are known to those skilled in the art and that drive or otherwise regulate gene expression. Such regulatory elements include but are not limited to the cytomegalovirus hCMV immediate early gene, the early or late promoters of SV40 adenovirus, the lac system, the trp system, the TAC system, the TRC system, the major operator and promoter regions of phage A, the control regions of fd coat protein, the promoter for 3-phosphoglycerate kinase, the promoters of acid phosphatase, and the promoters of the yeast .alpha.-mating factors.

"Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. In case of conflict, the present document, including definitions, will control. Preferred methods and materials are described below, although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. The materials, methods, and examples disclosed herein are illustrative only and not intended to be limiting.

"Other features and advantages of the invention, e.g., acellular tissue matrices that are useful for implantation in GT- subjects (e.g., human patients), will be apparent from the following description, from the drawings and from the claims."

URL and more information on this patent, see: McQuillan, David J.; Griffey, Edward S.; Beniker, Herbert Daniel; Xu, Hui. Acellular Tissue Matrices Made from .Alpha.-1,3-Galactose-Deficient Tissue. U.S. Patent Number 8802920, filed November 16, 2012, and published online on August 12, 2014. Patent URL: http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=8802920.PN.&OS=PN/8802920RS=PN/8802920

Keywords for this news article include: Legal Issues, Transferases, LifeCell Corporation, Enzymes and Coenzymes, Extracellular Matrix Proteins.

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Source: Life Science Weekly


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