Immune tolerance inducer
Inventors
Rii, Ko • Sakurai, Kazuo • Kobayashi, Masakazu • Ando, Hironori • Higuchi, Sadaharu • Takahara, Shiro
Assignees
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Publication Number
US-9801929-B2
Publication Date
2017-10-31
Expiration Date
Abstract
An object of the present invention is to provide a drug and a method for effectively inducing donor-specific immune tolerance in a recipient in transplantation therapy. A complex of an siRNA for a costimulatory factor and schizophyllan is delivered to a Dectin-1 expressing cell which specifically recognizes schizophyllan to regulate the function of the Dectin-1 expressing cell, and therefore can induce immunosuppression effect as well as induce immune tolerance effectively.
Core Innovation
The invention relates to an immunological tolerance inducer for transplantation therapy that comprises a nucleic acid-polysaccharide complex. The complex consists of an siRNA that inhibits CD40 gene expression, to which polydeoxyadenine is added, and schizophyllan is included, and is administered to an animal in need of immune tolerance for a donor cell, organ or tissue.
The nucleic acid-polysaccharide complex is delivered to Dectin-1-expressing antigen-presenting cells via Dectin-1 recognition of schizophyllan. In this context, RNAi-mediated inhibition of the target costimulatory factor suppresses immune activation and enables donor-specific immune tolerance.
Supported embodiments and rationale describe properties including Dicer resistance, activation, and stability in serum, and provide results in vitro, ex vivo and in vivo in cardiac transplantation models. The documented outcomes include improved graft function and adoptive transfer results indicating donor-specific immune tolerance.
Claims Coverage
The independent claim covers an intravenous method for inducing immune tolerance in transplantation therapy using a nucleic acid-polysaccharide complex that targets CD40 gene expression, together with polydeoxyadenine and schizophyllan. Across the dependent claims, the inventive features are refined by attachment and chemical modification of polydeoxyadenine and by narrowing the donor source and the transplantation therapy types.
Intravenous administration of an siRNA-polydeoxyadenine-schizophyllan complex
A method for inducing immune tolerance in transplantation therapy comprising intravenously administering a nucleic acid-polysaccharide complex to an animal in need of immune tolerance for a donor cell, organ or tissue.
siRNA inhibiting CD40 gene expression
The complex consists of an siRNA which inhibits CD40 gene expression.
Polydeoxyadenine added to the siRNA
Polydeoxyadenine is added to the siRNA.
Schizophyllan included in the complex
Schizophyllan is included in the complex.
Polydeoxyadenine attached to siRNA sense and antisense strands
Polydeoxyadenine is added to at least one end of both the siRNA sense strand and the siRNA antisense strand.
Phosphorothioated polydeoxyadenine
Polydeoxyadenine has at least a portion of its phosphodiester links phosphorothioated.
Donor cell derived from bone marrow
The donor cell, tissue, or organ is a cell derived from bone marrow.
Transplantation therapy selected from a defined list
The transplantation therapy is selected from kidney, heart, lung, bone marrow, skin, or corneal transplantation.
Overall claim coverage centers on a nucleic acid-polysaccharide complex delivered intravenously to induce immune tolerance in transplantation therapy. The core inventive content is an siRNA inhibiting CD40 gene expression combined with polydeoxyadenine and schizophyllan, with dependent features specifying polydeoxyadenine attachment and phosphorothioation and narrowing to bone-marrow-derived donor material and particular transplantation therapy categories.
Stated Advantages
Induces donor-specific immune tolerance by suppressing immune activation through RNAi-mediated inhibition of the target costimulatory factor.
Provides improved graft function and survival outcomes in cardiac transplantation models.
Adoptive transfer outcomes indicate donor-specific tolerance.
Documented Applications
Cardiac transplantation models including heterotopic cardiac transplantation, with results including improved graft beating/survival and donor-specific immune tolerance indicated by adoptive transfer.
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