DNA vaccines and methods for the prevention of transplantation rejection
Inventors
Li, Fengchun • Escher, Alan P.
Assignees
Publication Number
US-10500258-B2
Publication Date
2019-12-10
Expiration Date
2026-05-05
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Abstract
Methods for preventing, delaying the onset of, or treating rejection of an allograft using a DNA vaccine, where the vaccine can comprise a polynucleotide encoding a pro-apoptotic protein, like BAX and/or a polynucleotide encoding an autoantigen or donor antigen, like secreted glutamic acid decarboxylase 55. Administering one of the DNA vaccines to a transplant recipient, as described herein, can induce a donor specific tolerogenic response.
Core Innovation
The invention introduces methods for preventing, delaying the onset of, or treating rejection of an allograft by administering a DNA vaccine to a transplant recipient. The DNA vaccine can consist of one or more plasmids encoding specific proteins, including a polynucleotide encoding a pro-apoptotic protein such as BAX, and/or a polynucleotide encoding an autoantigen or donor antigen such as secreted glutamic acid decarboxylase 55. The DNA vaccine may be formulated as separate plasmids or combination constructs with methylated CpG motifs, which are designed to diminish unwanted immune responses.
The patent addresses the limitations of current immunosuppressive therapies, which provide only partial protection against acute rejection, do not prevent chronic rejection, and have broad side effects such as increased susceptibility to cancer and infection due to non-specific immunosuppression. Alternative strategies like co-stimulatory blockade and bone marrow chimerism also have drawbacks including late-onset chronic rejection and toxicities that limit clinical applicability.
The core of the innovation lies in using DNA vaccines to induce a donor-specific tolerogenic response. The method allows targeted immunoregulation by promoting physiological modulation of antigen presenting cell (APC) function via in vivo induction of apoptotic cells. This approach seeks to overcome the adverse effects associated with non-specific immunosuppression, offering the potential for increased graft survival and donor-specific immune tolerance.
Claims Coverage
There is one independent claim in this patent, with several main inventive features related to DNA vaccine compositions and their method of administration for preventing or minimizing transplant rejection.
Administration of a DNA vaccine composition comprising a first plasmid encoding a pro-apoptotic protein and a second plasmid encoding an autoantigen or donor antigen with methylated CpG motifs
The inventive method comprises intradermally administering to a graft or transplant recipient an effective amount of a DNA vaccine composition. The DNA vaccine composition includes: - A first plasmid with a polynucleotide encoding a pro-apoptotic protein (selected from BAX, Death Receptor 3, Death Receptor 4, Death Receptor 5, or a FAS receptor) operably linked to a promoter that controls its expression. - A second plasmid with a polynucleotide encoding an autoantigen or donor antigen operably linked to a promoter, and comprising a plurality of CpG motifs, wherein at least some of the CpG motifs are methylated and resistant to digestion by restriction endonuclease HpaII. This administration induces a tolerogenic response to prevent or minimize late-onset chronic graft or transplant rejection and/or transplant-induced autoimmunity.
The main inventive feature is the use of a two-plasmid DNA vaccine, with defined encoding sequences and methylated CpG motifs, to induce donor-specific tolerance and prevent or minimize chronic allograft rejection and transplant-associated autoimmunity.
Stated Advantages
Prevents, delays the onset of, or treats rejection of allografts or allogeneic transplants.
Reduces or eliminates the need for immunosuppressant drugs known to have serious long-term side-effects.
Induces a donor-specific tolerogenic immune response, targeting rejection without generalized immunosuppression.
Minimizes late-onset chronic graft or transplant rejection and transplant-induced autoimmunity.
Documented Applications
Prevention, delay of onset, or treatment of rejection in skin grafts, islet cell transplants, and partial or whole organ transplants.
Application to organ transplants selected from hearts, lungs, kidneys, and livers.
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