Gene and oligonucleotide therapies have the potential to revolutionize the treatment of many diseases. However, the safety of these new drugs is a major issue. Of particular concern, many gene-based medicines trigger activation of the innate immune system. This results in the release of highly inflammatory cytokines, such as type I interferons and IL-6, which can be toxic to the recipient, and even deadly. The innate response also initiates an adaptive immune response that results in production of antibodies against the therapeutic transgene product, as well as cytotoxic T cells that can kill cells expressing the replacement gene, and eliminate the benefits of the therapy. Even though compound-specific modifications to gene-based drugs can sometimes prevent the innate response, a more general approach is greatly needed to improve the safety and efficacy of gene and oligonucleotide therapy. Our long-term goal is to develop a means to prevent the inflammatory response to gene-based drugs, and to use gene transfer to induce antigen-specific tolerance for preventing unwanted immune responses. The objectives of this project are: (i) to identify molecular and cellular pathways that control the innate response to oligonucleotides and gene vectors, (ii) to target these pathways to dampen the innate response to gene delivery, and (ii) to exploit this effect for inducing immunological tolerance. In recent studies, we have discovered that the miR-126-VEGFR2 axis serves as an essential pathway required for the innate response to nucleic acids (Agudo et al. Nature Immunology 2014). Based on our findings, we hypothesize that the miR-126-VEGF signaling pathway controls the homeostasis and function of a subset of plasmacytoid dendritic cells (pDC) that are responsible for recognizing and initiating the inflammatory response to therapeutic DNA and RNA, and that blocking this pathway, using clinically approved drugs, can blunt both the innate and adaptive immune response to specific gene-based drugs, including lentiviral vectors and short interfering RNAs (siRNA). To test our hypotheses, we will: (1) Identify the function of mouse and human miR-126 in the innate response to therapeutic vectors and oligonucleotides, (2) determine the impact of modulating mouse and human VEGFR2 signaling on the inflammatory response to therapeutic nucleic acids, and (3) evaluate whether targeting antigen to a new pDC subset that we have identified which are not activated by nucleic acids, can promote antigen-specific immune tolerance. The results of our studies will: uncover new insights into innate immunity, particularly related to the interactions between nucleic acids and DCs, provide a clinically applicable means to prevent the inflammatory response to some gene and oligo-based therapies, and establish a strategy for inducing tolerance to an antigen, which will form the basis of a vaccine for reversing autoimmunity and for preventing the immune response to replacement coagulation factor in hemophiliacs.

Public Health Relevance

Gene and oligo therapies have incredible potential to treat, and even cure, a variety of diseases, including hemophilia. Unfortunately, one of the major problems is that RNA and DNA-based drugs can activate the immune system, causing harmful toxicity and even rejection. The objective of this project is to identify molecular and cellular pathways that control the innate response to oligos and gene vectors, to target these pathways to dampen the innate response to gene delivery, and to exploit this effect for inducing immune tolerance.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Gene and Drug Delivery Systems Study Section (GDD)
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Jiang, Chao
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Icahn School of Medicine at Mount Sinai
Schools of Medicine
New York
United States
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