ADAMTS13 treatment to enhance graft survival
View Patent ↗The disclosure provides a method for treating and/or preventing graft rejection with A Disintegrin And Metalloproteinase with Thrombospondin type 1 motif, member-13 (ADAMT S13). The disclosure provides a method for increasing ADAMTS13-mediated von Willebrand factor (VWF) cleavage in a subject that received a graft by administering ADAMTS13. The disclosure also provides a method of determining the likelihood that a subject will rejection a graft.
1 . A method for treating or preventing graft rejection in a subject that received a skin graft, the method comprising administering to the subject in need thereof a therapeutically effective amount of a composition comprising A Disintegrin And Metalloproteinase with Thrombospondin type 1 motif, member-13 (ADAMTS13), wherein administering ADAMTS13 reduces and/or prevents neutrophil extracellular trap (NET) burden in the skin graft.
2 . The method of claim 1 , wherein the subject is administered ADAMTS13 after at least one symptom of graft rejection is present, or wherein the subject is administered ADAMTS13 before a symptom of graft rejection is present.
3 . The method of claim 1 , wherein administering ADAMTS13 reduces and/or prevents at least one of graft deterioration, graft desiccation, graft shrinkage, scab formation, graft hardening, loss of hair, graft dysfunction, organ deterioration, organ damage, organ dysfunction, cell damage, inflammation, swelling, erythema, seroma, severity of pain, infection, neutrophil recruitment, lymphocyte recruitment, platelet aggregation, microthrombosis, generation of angiogenesis or a combination of any thereof as compared to control, the subject without treatment, and/or the subject before transplantation.
4 . The method of claim 3 , wherein the lymphocyte recruitment is T-cell recruitment.
5 . The claim of claim 3 , wherein the level of NET burden is determined by measuring the level of histone modifications, cell-free DNA, citrullinated histone H3 (H3Cit), citrullinated histone H4 (H4Cit), neutrophil elastase (NE), and/or myeloperoxidase (MPO) DNA conjugates.
6 . The method of claim 1 , wherein administering ADAMTS13 results in at least one of increased survival of the graft, improved organ function, increased survival of the subject, or a combination of any thereof as compared to control, the subject without treatment, and/or the subject before transplantation.
7 . The method of claim 1 , wherein the therapeutically effective amount of ADAMTS13 is from about 20 to about 6,000 international units per kilogram body weight.
8 . The method of claim 1 , wherein the composition comprising ADAMTS13 is administered in a single bolus injection, monthly, every two weeks, weekly, twice a week, daily, every twelve hours, every eight hours, every six hours, every four hours, or every two hours, and wherein the composition comprising ADAMTS13 is administered intravenously, subcutaneously, or dermally.
9 . The method of claim 1 , wherein the ADAMTS13 is recombinant ADAMTS13, or wherein the ADAMTS13 is plasma derived.
10 . The method of claim 1 , wherein the subject is a mammal or wherein the subject is a human.
11 . The method of claim 1 , wherein the composition is in a stable aqueous solution ready for administration.
12 . The method of claim 1 , wherein the therapeutically effective amount of the composition comprising ADAMTS13: is administered to the subject within 48 hours after receiving the graft, or is sufficient to maintain an effective level of ADAMTS13 activity in the subject.
13 . The method of claim 1 , wherein the graft is an allograft; an autograft; a xenograft obtained from a pig, a primate, or a cow; an artificially manufactured device; or wherein the graft is transplanted to the subject that is suffering from a wound, a burn, a damaged organ, or an infection, and/or the subject has undergone surgery.
14 . The method of claim 1 , further comprising modifying one or more additional genes or gene products such that the expression and/or function of said additional gene(s) or gene product(s) is reduced or eliminated, wherein said additional gene(s) or gene product(s) are PAD4, H3Cit, H4Cit, MPO, NE, or NLRP3.
15 . The method of claim 14 , wherein the modifying of one or more additional genes comprises: disrupting said gene(s) with a site-specific nuclease; administering an RNA interference (RNAi) molecule or an antisense oligonucleotide; or administering one or more of a small molecule inhibitor, a peptide, an antibody or antibody fragment, and an aptamer.
16 . The method of claim 15 , wherein the site-specific nuclease comprises a Cas protein and a guide RNA, a zinc finger nuclease (ZFN), a TALEN nuclease, or a mega-TALEN nuclease; or wherein the RNAi molecule is a small interfering RNA (siRNA) or a small hairpin RNA (shRNA).
17 . The method of claim 1 , further comprising inhibiting NET formation and/or neutrophil infiltration.
18 . The method of claim 17 , wherein the inhibiting NET formation comprises: administering one or more of a small molecule inhibitor, a peptide, an antibody or antibody fragment, and an aptamer; or by administering, increasing the expression of, and/or activating DNase 1.