Nucleic acid/polysaccharide complex
Inventors
Rii, Ko • Sakurai, Kazuo • Kobayashi, Masakazu • Ando, Hironori • Higuchi, Sadaharu • Takahara, Shiro
Assignees
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Publication Number
US-9713636-B2
Publication Date
2017-07-25
Expiration Date
Abstract
A highly stable nucleic acid-polysaccharide complex of an siRNA and schizophyllan is formed by adding polydeoxyadenine in which at least part of the phosphodiester link portion is phosphorothioated to an siRNA and allowing the siRNA and schizophyllan to form a complex.
Core Innovation
The disclosure describes a highly stable nucleic acid–polysaccharide complex formed by adding polydeoxyadenine (poly(dA)) to an siRNA and complexing with schizophyllan (SPG), wherein at least part of the poly(dA) phosphodiester bonds are phosphorothioated (S-modified poly(dA)). The nucleic acid–polysaccharide complex is presented as a way to address limitations of prior SPG–poly(dA)/siRNA complexes, including steric hindrance and inability to access RISC.
The SPG-mediated delivery targets Dectin-1–expressing antigen-presenting cells, thereby modulating their function and enabling effective RNA interference in Dectin-1 cells. The disclosure focuses on suppressing gene expression against costimulatory factors such as Cluster of Differentiation 40 (CD40), including CD40-associated immunomodulatory effects in the context of resistance or rejection in transplantation therapy.
Example findings reported in the disclosure include stability in serum, Dicer non-cleavability for 21-mer siRNAs with S-modified poly(dA), restoration of RNAi activity, reduced Dectin-1/CD40 expression, and inhibition of lymphocyte activation in a mixed lymphocyte reaction (MLR). The disclosure also reports improved outcomes in a heterotopic cardiac transplantation model using a dA40(s)-siCD40(21 nt)/SPG complex.
Claims Coverage
The provided independent claim covers a method for suppressing rejection in transplantation therapy by administering a defined SPG–poly(dA)-modified siRNA complex targeting a specific costimulatory factor (CD40). Dependent claims refine the molecular composition and narrow the therapeutic context to particular transplantation types, with five inventive features in total.
Intravenous administration of an SPG–poly(dA)/siRNA complex for transplant rejection suppression
A method for suppressing rejection occurring in transplantation therapy, comprising intravenously administering a nucleic acid-polysaccharide complex of schizophyllan and a polynucleotide containing an siRNA to which polydeoxyadenine is added, to an animal in need of treatment or prophylaxis of resistance or rejection to a transplanted organ or tissue.
Targeting CD40 costimulatory factor with siRNA to suppress rejection
The nucleic acid-polysaccharide complex is administered wherein the siRNA is against a costimulatory factor, and the costimulatory factor is Cluster of Differentiation 40 (CD40).
21-mer siRNA with S-modified polydeoxyadenine added to the siRNA sense strand
The method wherein the siRNA is a 21mer type and the polynucleotide contains polydeoxyadenine with phosphodiester links at least partially phosphorothioated, added to a sense strand of the siRNA.
Polydeoxyadenine having at least 50% phosphorothioated phosphodiester links
The method wherein polydeoxyadenine has at least 50% of its phosphodiester links phosphorothioated.
Transplantation therapy for specified organ and tissue types
The method wherein the transplantation therapy is for kidney transplantation, heart transplantation, lung transplantation, bone marrow transplantation, skin transplantation, or corneal transplantation.
Overall, the claim coverage centers on intravenous delivery of a schizophyllan nucleic acid–polysaccharide complex comprising siRNA with polydeoxyadenine added, including S-modified/phosphorothioated poly(dA), where the siRNA targets the CD40 costimulatory factor to provide treatment or prophylaxis for resistance or rejection in transplantation therapy. Dependent claims further specify a 21-mer siRNA composition, a quantitative phosphorothioation threshold, and particular transplant organ/tissue types.
Stated Advantages
Provides treatment or prophylaxis of resistance or rejection to a transplanted organ or tissue.
Enables effective RNA interference against genes in Dectin-1 cells.
Results in stability in serum and Dicer non-cleavability for 21-mer siRNAs with S-modified poly(dA).
Restores RNAi activity while reducing Dectin-1/CD40 expression.
Inhibits lymphocyte activation in mixed lymphocyte reaction (MLR).
Improves outcomes in a heterotopic cardiac transplantation model.
Documented Applications
Suppressing rejection in transplantation therapy by targeting the CD40 costimulatory factor using a dA40(s)-siCD40(21 nt)/SPG complex.
Application to a heterotopic cardiac transplantation model to improve transplantation outcomes.
Application to transplantation contexts including kidney transplantation, heart transplantation, lung transplantation, bone marrow transplantation, skin transplantation, and corneal transplantation.
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