Use of regeneration factors in organ transplantation
Ex vivo treatment methods and materials restore and regenerate damaged organs for transplantation, addressing various forms of injury to increase the donor organ bank and improve transplant suitability.
Patent Information
- Application Number
- HK62026123751
- Authority / Receiving Office
- HK · HK
- Patent Type
- Applications
- Current Assignee / Owner
- Priority Date
- 2023-01-19
- Filing Date
- 2026-05-21
- Publication Date
- 2026-07-31
AI Technical Summary
Existing methods fail to effectively restore and regenerate aged or damaged organs for transplantation, such as kidneys and livers, due to ischemic, toxic, hypertensive, immune, physical, and other forms of injury, limiting the availability of donor organs.
Ex vivo treatment methods and materials are used to treat and regenerate organs prior to transplantation, addressing specific types of damage including ischemic, toxic, hypertensive, immune, physical, and fibrosis unrelated to known causes, thereby increasing the usable donor organ bank.
The methods and materials enhance the quality and availability of donor organs by restoring and regenerating organs to a transplantable state, improving their functional integrity and reducing damage-related limitations.
Smart Images
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Abstract
Description
This abstract provides materials and methods for restoring ex vivo organs before transplantation into a recipient. The methods and materials can be used to treat, improve, restore, and / or regenerate organs, such as kidneys and livers, that are aged and / or characterized by organ damage caused by ischemic injury, toxic injury, perfusion injury, hypertensive injury, immune injury, physical injury, fatty degeneration, virus-induced hepatitis, alcohol, or fibrosis unrelated to any known cause. The provided materials and methods can increase the available donor organ bank, such as kidneys and livers. Furthermore, the provided materials and methods can treat organs subsequently transplanted autologously.
Claims
WHAT IS CLAIMED IS:
1. An organ perfusate comprising a first polynucleotide encoding at least one regeneration factor and at least one vasodilator.
2. The organ perfusate of claim 1, wherein the first polynucleotide encoding the at least one regeneration factor is operably linked to a promoter.
3. The organ perfusate of claim 1 or 2, further comprising at least one tonicity agent.
4. The organ perfusate of any one of claims 1-3, further comprising at least one of a buffer, an inorganic salt, an amino acid, a substrate for metabolism, a hormone, an anti-oxidant, an anti-inflammatory agent, an anti-coagulant, or an anti-microbial agent.
5. The organ perfusate of any one of claims 1-3, further comprising human serum albumin, dextran, and an extracellular electrolyte composition.
6. The organ perfusate of any one of claims 3-5, wherein the tonicity agent is selected from the group consisting of dextrose, glycerin, mannitol, potassium chloride, sodium chloride, and combinations thereof.
7. The organ perfusate of any one of claims 1-6, wherein the vasodilator is selected from the group consisting of carbon monoxide, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin receptor blocker, a calcium channel blocker, prostacyclin, hydralazine, minoxidil, nitroglycerin, and combinations thereof.
8. The organ perfusate of any one of claims 1-7, further comprising an oxygenation agent.
9. The organ perfusate of claim 8, wherein the oxygenation agent is selected from the group consisting of a red blood cell, hemoglobin, pyridoxylated hemoglobin, a synthetic hemoglobin-based oxygen carrier, and combinations thereof.
10. The organ perfusate of claim 9, wherein the synthetic hemoglobin-based oxygen carrier is a polymerized hemoglobin-based oxygen carrier, Lifor™, Aquix RS-I, Hemarina®, or Perfluorocarbon.
11. The organ perfusate of any one of claims 1-10, further comprising a second polynucleotide encoding at least one regeneration factor operably linked to a promoter.
12. The organ perfusate of any one of claims 1-11, wherein the promoter of the first polynucleotide and the second polynucleotide are inducible promoters.
13. The organ perfusate of any one of claims 1-12, wherein the at least one regeneration factor encoded by the first polynucleotide is selected from the group consisting of an Oct family transcription factor, a Sox family transcription factor, a Klf family transcription factor, and a Myc family transcription factor.
14. The organ perfusate of any one of claims 11-13, wherein the at least one regeneration factor encoded by the second polynucleotide is selected from the group consisting of an Oct family transcription factor, a Sox family transcription factor, a Klf family transcription factor, and a Myc family transcription factor.
15. The organ perfusate of claim 13 or 14, wherein the Oct family transcription factor is selected from the group consisting of Octi, Oct3, Oct4, Oct6, and variants thereof.
16. The organ perfusate of claim 13 or 14, wherein the Sox family transcription factor is selected from the group consisting of Soxl, Sox2, Sox3, Sox7, Soxl5, Soxl7, Soxl8, and variants thereof.
17. The organ perfusate of claim 13 or 14, wherein the Klf family transcription factor is selected from the group consisting of Kfll, Klf4, Klf5, and variants thereof.
18. The organ perfusate of claim 13 or 14, wherein the Myc family transcription factor is selected from the group consisting of c-Myc, L-Myc, N-Myc, and variants thereof.
19. The organ perfusate of any one of claims 1-18, wherein the first polynucleotide, the second polynucleotide, or both, are encapsulated in a nanoparticle.
20. The organ perfusate of claim 19, wherein the nanoparticle is a lipid nanoparticle, a polymeric nanoparticle, a ligand-conjugated lipid nanoparticle, or a ligand-conjugated polymeric nanoparticle.
21. The organ perfusate of any one of claims 1-20, wherein the first polynucleotide, the second polynucleotide, or both, are present within a viral genome, a plasmid, a minicircle vector, or a transposon.
22. The organ perfusate of claim 21, wherein the viral genome is selected from an AAV genome, an adenoviral genome, a retroviral genome, or a lentiviral genome.
23. The organ perfusate of any one of claims 1-22, wherein the perfusate further comprises a regeneration factor-protein transfer domain fusion protein.
24. The organ perfusate of any one of claims 1-23, wherein the perfusate further comprises a regeneration factor polypeptide.
25. The organ perfusate of any one of claims 1-24, wherein the perfusate further comprises an Oct family transcription factor, a Sox family transcription factor, a Klf family transcription factor, and / or a Myc family transcription factor.
26. The organ perfusate of claim 25, wherein the Oct family transcription factor is selected from the group consisting of Octi, Oct3, Oct4, Oct6, and variants thereof.
27. The organ perfusate of claim 25 or 26, wherein the Sox family transcription factor is selected from the group consisting of Soxl, Sox2, Sox3, Sox7, Soxl5, Soxl7, Soxl8, and variants thereof.
28. The organ perfusate of any one of claims 25-27, wherein the Klf family transcription factor is selected from the group consisting of Kfll, Klf4, Klf5, and variants thereof.
29. The organ perfusate of any one of claims 25-28, wherein the Myc family transcription factor is selected from the group consisting of c-Myc, L-Myc, N-Myc, and variants thereof.
30. The organ perfusate of any one of claims 1-29, further comprising an enhancing agent selected from the group consisting of soluble Wnt, Wnt conditioned media, BIX-01294 (a G9a histone methyltransferase), PD0325901 (a MEK inhibitor), DNA methyltransferase inhibitors, histone deacetylase (HD AC) inhibitors, valproic acid, 5'-azacytidine, dexamethasone, suberoylanilide, hydroxamic acid (SAHA), vitamin C, and trichostatin (TSA), and combinations thereof.
31. A method of ex vivo rejuvenation of an organ, the method comprising:(a) providing an organ;(b) contacting the organ ex vivo with a composition comprising a polynucleotide encoding at least one regeneration factor operably linked to an inducible promoter; and(c) adding to the composition a compound that induces the inducible promoter to promote expression of the at least one regeneration factor, whereby the at least one regeneration factor is expressed and the organ is rejuvenated.
32. The method of claim 31, wherein the compound is added intermittently.
33. The method of claim 32, wherein the intermittent addition comprises adding the compound once per day on two consecutive days and not adding the agent on the following 5 consecutive days.
34. The method of claims 31 or 32, wherein the intermittent addition is performed 2-10 times.
35. The method of claim 34, wherein the intermittent addition is performed 2-10 times over a period of about 1 week to about 6 weeks.
36. The method of any one of claims 31-35, wherein the composition further comprises a vasodilator.
37. The method of any one of claims 31-36, wherein the composition further comprises a tonicity agent.
38. The method of any one of claims 31-37, wherein the composition further comprises at least one of a buffer, an inorganic salt, an amino acid, a substrate for metabolism, a hormone, an anti-oxidant, an anti-inflammatory agent, an anti-coagulant, or an antimicrobial agent.
39. The method of any one of claims 31-38, wherein the organ is provided in a perfusion system selected from a Hugo-Sachs system, an Organ Assist system, an OrganOX system, a Radnoti system, an ARK Kidney system, and Aferetica PerLife® system.
40. The method of any one of claims 31-39, wherein the organ is a kidney or a liver.
41. A method of transplanting an organ into a subject in need thereof, the method comprising:(a) providing an organ;(b) contacting the organ ex vivo with a composition comprising a polynucleotide encoding at least one regeneration factor operably linked to an inducible promoter;(c) adding to the composition a compound that induces the inducible promoter; and(d) transplanting the organ into the subject.
42. The method of claim 41, wherein the compound is added for about 1 minute to about 24 hours to the composition.
43. The method of claim 41 or 42, wherein the compound is added intermittently to the composition.
44. The method of claim 43, wherein the intermittent addition of the compound comprises adding the compound once per day on two consecutive days and not adding the compound on the following 5 consecutive days.
45. The method of 44, wherein the intermittent addition of the compound is repeated 2-10 times.
46. The method of claim 45, wherein the intermittent addition is performed 2-10 times over a period of about 1 week to about 6 weeks.
47. A method of transplanting an organ into a subject in need thereof, the method comprising:(a) providing an organ;(b) contacting the organ ex vivo with a composition comprising a polynucleotide encoding at least one regeneration factor operably linked to an inducible promoter;(c) transplanting the organ into the subject; and(d) administering to the subject a compound that induces the inducible promoter.
48. The method of claim 47, wherein the compound is administered for about 1 minute to about 24 hours to the subject.
49. The method of claim 47 or 48, wherein the compound is administered intermittently to the subject.
50. The method of claim 49, wherein the intermittent administration of the compound comprises administering the compound once per day on two consecutive days and not administering the compound on the following 5 consecutive days.
51. The method of claim 49 or 50, wherein the intermittent administration of the compound is repeated about 2-10 times.
52. The method of claim 51, wherein the intermittent administration of the compound is performed about 2-10 times every 3 months.
53. The method of claim 52, wherein the intermittent administration of the compound is performed about 2-10 times every 6 months.
54. The method of any one of claims 31-53, wherein the composition further comprises a vasodilator.
55. The method of any one of claims 31-54, wherein the composition further comprises a tonicity agent.
56. The method of any one of claims 31-55, further comprising at least one of a buffer, an inorganic salt, an amino acid, a substrate for metabolism, a hormone, an anti-oxidant, an anti-inflammatory agent, an anti-coagulant, or an anti-microbial agent.
57. The method of any one of claims 31-56, wherein the explanted organ is provided in a perfusion system selected from a Hugo-Sachs system, an Organ Assist system, an OrganOX system, a Radnoti system, an ARK Kidney system, and Aferetica PerLife® system.
58. The method of any one of claims 31-57, wherein the organ is a kidney or a liver.
59. The method of any one of claims 31-58, wherein the method further comprises taking a biopsy from the organ prior to being transplanted.
60. The method of any one of claims 31-58, wherein the method further comprises taking a biopsy of the organ after being transplanted.
61. The method of any one of claims 31-60, further comprising monitoring the subject who has been transplanted with the organ for organ function.
62. The method of claim 61, wherein the monitoring comprises measuring one or more of blood urea levels, serum creatinine levels, bilirubin levels, blood pH, blood bicarbonate levels, blood sodium levels, blood potassium levels, or blood lactate levels.
63. The method of any one of claims 31-62, further comprising administering an immunosuppressive medication to the subject.
64. An ex vivo organ for transplantation to a subject in need thereof, the ex vivo organ comprising: (i) a perfusate; and (ii) a polynucleotide encoding at least one regeneration factor.
65. The ex vivo organ of claim 64, wherein the ex vivo organ is damaged by at least one of old age, an ischemic injury, a hypertensive injury, a toxic injury, a perfusion injury, an immune injury, a physical injury, steatosis, virus induced hepatitis, alcohol, or a fibrosis not associated with any known cause.
66. The ex vivo organ of claim 64 or 65, wherein the polynucleotide further comprises an inducible promoter operably linked to the polynucleotide encoding the at least one regeneration factor.
67. The ex vivo organ of any one of claims 64-66, wherein the perfusate intermittently comprises a compound that induces the inducible promoter.