Overcoming innate immune barriers that impede AAV gene therapy vectors

UMMS Affiliation

Horae Gene Therapy Center; Department of Microbiology and Physiological Systems; VIDE Program; Department of Medicine, Division of Infectious Diseases and Immunology; Program in Innate Immunity; Li Weibo Institute for Rare Diseases Research

Publication Date


Document Type



Genetics and Genomics | Hemic and Immune Systems | Immunity | Immunoprophylaxis and Therapy | Immunotherapy | Microbiology | Virology | Viruses


The field of gene therapy has made considerable progress over the past several years. Adeno-associated virus (AAV) vectors have emerged as promising and attractive tools for in vivo gene therapy. Despite the recent clinical successes achieved with recombinant AAVs (rAAVs) for therapeutics, host immune responses against the vector and transgene product have been observed in numerous preclinical and clinical studies. These outcomes have hampered the advancement of AAV gene therapies, preventing them from becoming fully viable and safe medicines. The human immune system is multidimensional and complex. Both the innate and adaptive arms of the immune system seem to play a concerted role in the response against rAAVs. While most efforts have been focused on the role of adaptive immunity and developing ways to overcome it, the innate immune system has also been found to have a critical function. Innate immunity not only mediates the initial response to the vector, but also primes the adaptive immune system to launch a more deleterious attack against the foreign vector. This Review highlights what is known about innate immune responses against rAAVs and discusses potential strategies to circumvent these pathways.


gene therapy, innate immune responses, AAVs, adeno-associated viruses

DOI of Published Version



Muhuri M, Maeda Y, Ma H, Ram S, Fitzgerald KA, Tai PW, Gao G. Overcoming innate immune barriers that impede AAV gene therapy vectors. J Clin Invest. 2021 Jan 4;131(1):e143780. doi: 10.1172/JCI143780. PMID: 33393506; PMCID: PMC7773343. Link to article on publisher's site

Journal/Book/Conference Title

The Journal of clinical investigation

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Link to Article in PubMed

PubMed ID