Tissue products derived from animals lacking any expression of functional alpha 1, 3 galactosyltransferase

• US 10,130,737 B2
• Filed: 08/01/2014
• Issued: 11/20/2018
• Est. Priority Date: 08/21/2002
• Status: Expired due to Term

• Current Assignee: Revivicor, Inc (United Therapeutics Corporation)
• Original Assignee: Revivicor, Inc (United Therapeutics Corporation)
• Inventors: Ayares, David, Rohricht, Paul
• Primary Examiner(s): Singh, Anoop K
• Assistant Examiner(s): Sgagias, Magdalene K
• Application Number:
  US14/449,969
• Publication Number:
  US 20150182664A1
• Time in Patent Office: 1,572 Days
• CPC Class Codes: A01K 2217/075 inducing loss of function, i.e. knock out
• CPC Class Codes: A01K 2227/108 Swine
• CPC Class Codes: A01K 2267/02 Animal zootechnically ameliorated
• CPC Class Codes: A01K 2267/025 Animal producing cells or organs for transplantation
• CPC Class Codes: A01K 67/0276 Knock-out vertebrates
• CPC Class Codes: A61K 35/12 Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells vaccines or medicinal preparations containing antigens or antibodies A61K39/00
• CPC Class Codes: A61L 2430/34 for soft tissue reconstruction
• CPC Class Codes: A61L 27/3604 characterised by the human or animal origin of the biological material, e.g. hair, fascia, fish scales, silk, shellac, pericardium, pleura, renal tissue, amniotic membrane, parenchymal tissue, fetal tissue, muscle tissue, fat tissue, enamel
• CPC Class Codes: A61L 27/3629 Intestinal tissue, e.g. small intestinal submucosa
• CPC Class Codes: A61L 27/3641 characterised by the site of application in the body materials for artificial blood vessels A61L27/507; materials for use in artificial skin A61L27/60
• CPC Class Codes: A61L 27/3683 subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment
• CPC Class Codes: A61L 27/3695 characterised by the function or physical properties of the final product, where no specific conditions are defined to achieve this A61L27/3687, A61L27/3691 take precedence
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: C12N 15/8509 for producing genetically modified animals, e.g. transgenic
• CPC Class Codes: C12N 9/1051 Hexosyltransferases (2.4.1)

Abstract

The present invention provides tissues derived from animals, which lack any expression of functional alpha 1,3 galactosyltransferase (alpha-1,3-GT). Such tissues can be used in the field of xenotransplantation, such as orthopedic reconstruction and repair, skin repair and internal tissue repair or as medical devices.

Claims

1. A tissue product comprising a tissue stripped of viable cells wherein the tissue is derived from a tissue of a porcine animal in which both alleles of the alpha-1,3-galactosyltransferase gene are inactive, wherein at least one allele is rendered inactive through at least one point mutation, and the animal lacks expression of alpha-1,3-galactosyltransferase.

2. The tissue product of claim 1, wherein the tissue is a hard tissue.

3. The tissue product of claim 1, wherein the tissue is a soft tissue.

4. The tissue product of claim 2, wherein the hard tissue is bone or a fragment or derivative thereof.

5. The tissue product of claim 3, wherein the soft tissue is selected from the group consisting of skin, dermal, submucosal, ligament, tendon and cartilage or a fragment or derivative thereof.

6. The tissue product of claim 1, wherein the tissue is a combination of hard and soft tissue.

7. The tissue product of claim 6, wherein the tissue is a bone-tendon-bone graft.

8. The tissue product of claim 1, wherein at least one allele of the alpha-1,3-GT gene is rendered inactive by a genetic targeting event.

9. The tissue product of claim 8, wherein the genetic targeting event is homologous recombination.

10. The tissue product of claim 8 or 9, wherein the genetic targeting event uses a targeting construct directed to exon 9 of the alpha-1,3-GT gene.

11. The tissue product of claim 8, wherein both alleles of the alpha-1,3-GT gene are rendered inactive through at least one point mutation.

12. The tissue product of claim 8, wherein the at least one point mutation of the alpha-1,3-GT gene is a substitution, deletion or insertion mutation or a combination thereof.

13. The tissue product of claim 8, wherein at least one point mutation of the alpha-1,3-GT gene is a T-to-G point mutation at the second base of exon 9.

14. The tissue product of claim 13, wherein the T-to-G point mutation at the second base of exon 9 in both alleles of the alpha-1,3-GT gene.

15. The tissue product of claim 8, wherein an allele of the alpha-1,3-GT gene is rendered inactive through at least two point mutations.

16. The tissue product of claim 8, wherein the tissue stripped of viable cells is produced by enzymatic treatment.

17. The tissue product of claim 8, wherein the tissue is bone.

18. The tissue product of claim 8, wherein the tissue stripped of viable cells is produced by chemical treatment.

19. The tissue product of claim 8, wherein the tissue is selected from the group consisting of tendon, joint, bone and heart valve.

20. The tissue product of claim 9 or 11, wherein the tissue can be further processed via crosslinking treatments.

21. The tissue product of claim 17 or 19, wherein the tissue can be further processed via additional chemical treatments.