Overcoming innate immune barriers that impede AAV gene therapy vectors
Manish Muhuri,1,2,3 Yukiko Maeda,1,3,4 Hong Ma,1 Sanjay Ram,5 Katherine A. Fitzgerald,6 Phillip W.L. Tai,1,2,3 and Guangping Gao1,2,7
1Horae Gene Therapy Center,
2Department of Microbiology and Physiological Systems,
3VIDE Program,
4Department of Medicine,
5Division of Infectious Diseases and Immunology,
6Program in Innate Immunity, Department of Medicine, and
7Li Weibo Institute for Rare Diseases Research, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Address correspondence to: Guangping Gao or Phillip W.L. Tai, Horae Gene Therapy Center, University of Massachusetts Medical School, 386 Plantation Street, Worcester, Massachusetts 01605, USA. Phone: 508.856.3394; Email: guangping.gao@umassmed.edu (GG). Phone: 774.455.4559; Email: Phillip.Tai2@umassmed.edu (PWLT).
Authorship note: MM and YM contributed equally to this work.
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1Horae Gene Therapy Center,
2Department of Microbiology and Physiological Systems,
3VIDE Program,
4Department of Medicine,
5Division of Infectious Diseases and Immunology,
6Program in Innate Immunity, Department of Medicine, and
7Li Weibo Institute for Rare Diseases Research, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Address correspondence to: Guangping Gao or Phillip W.L. Tai, Horae Gene Therapy Center, University of Massachusetts Medical School, 386 Plantation Street, Worcester, Massachusetts 01605, USA. Phone: 508.856.3394; Email: guangping.gao@umassmed.edu (GG). Phone: 774.455.4559; Email: Phillip.Tai2@umassmed.edu (PWLT).
Authorship note: MM and YM contributed equally to this work.
Find articles by Maeda, Y. in: JCI | PubMed | Google Scholar
1Horae Gene Therapy Center,
2Department of Microbiology and Physiological Systems,
3VIDE Program,
4Department of Medicine,
5Division of Infectious Diseases and Immunology,
6Program in Innate Immunity, Department of Medicine, and
7Li Weibo Institute for Rare Diseases Research, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Address correspondence to: Guangping Gao or Phillip W.L. Tai, Horae Gene Therapy Center, University of Massachusetts Medical School, 386 Plantation Street, Worcester, Massachusetts 01605, USA. Phone: 508.856.3394; Email: guangping.gao@umassmed.edu (GG). Phone: 774.455.4559; Email: Phillip.Tai2@umassmed.edu (PWLT).
Authorship note: MM and YM contributed equally to this work.
Find articles by Ma, H. in: JCI | PubMed | Google Scholar
1Horae Gene Therapy Center,
2Department of Microbiology and Physiological Systems,
3VIDE Program,
4Department of Medicine,
5Division of Infectious Diseases and Immunology,
6Program in Innate Immunity, Department of Medicine, and
7Li Weibo Institute for Rare Diseases Research, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Address correspondence to: Guangping Gao or Phillip W.L. Tai, Horae Gene Therapy Center, University of Massachusetts Medical School, 386 Plantation Street, Worcester, Massachusetts 01605, USA. Phone: 508.856.3394; Email: guangping.gao@umassmed.edu (GG). Phone: 774.455.4559; Email: Phillip.Tai2@umassmed.edu (PWLT).
Authorship note: MM and YM contributed equally to this work.
Find articles by Ram, S. in: JCI | PubMed | Google Scholar
1Horae Gene Therapy Center,
2Department of Microbiology and Physiological Systems,
3VIDE Program,
4Department of Medicine,
5Division of Infectious Diseases and Immunology,
6Program in Innate Immunity, Department of Medicine, and
7Li Weibo Institute for Rare Diseases Research, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Address correspondence to: Guangping Gao or Phillip W.L. Tai, Horae Gene Therapy Center, University of Massachusetts Medical School, 386 Plantation Street, Worcester, Massachusetts 01605, USA. Phone: 508.856.3394; Email: guangping.gao@umassmed.edu (GG). Phone: 774.455.4559; Email: Phillip.Tai2@umassmed.edu (PWLT).
Authorship note: MM and YM contributed equally to this work.
Find articles by Fitzgerald, K. in: JCI | PubMed | Google Scholar
1Horae Gene Therapy Center,
2Department of Microbiology and Physiological Systems,
3VIDE Program,
4Department of Medicine,
5Division of Infectious Diseases and Immunology,
6Program in Innate Immunity, Department of Medicine, and
7Li Weibo Institute for Rare Diseases Research, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Address correspondence to: Guangping Gao or Phillip W.L. Tai, Horae Gene Therapy Center, University of Massachusetts Medical School, 386 Plantation Street, Worcester, Massachusetts 01605, USA. Phone: 508.856.3394; Email: guangping.gao@umassmed.edu (GG). Phone: 774.455.4559; Email: Phillip.Tai2@umassmed.edu (PWLT).
Authorship note: MM and YM contributed equally to this work.
Find articles by Tai, P. in: JCI | PubMed | Google Scholar
1Horae Gene Therapy Center,
2Department of Microbiology and Physiological Systems,
3VIDE Program,
4Department of Medicine,
5Division of Infectious Diseases and Immunology,
6Program in Innate Immunity, Department of Medicine, and
7Li Weibo Institute for Rare Diseases Research, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Address correspondence to: Guangping Gao or Phillip W.L. Tai, Horae Gene Therapy Center, University of Massachusetts Medical School, 386 Plantation Street, Worcester, Massachusetts 01605, USA. Phone: 508.856.3394; Email: guangping.gao@umassmed.edu (GG). Phone: 774.455.4559; Email: Phillip.Tai2@umassmed.edu (PWLT).
Authorship note: MM and YM contributed equally to this work.
Find articles by Gao, G. in: JCI | PubMed | Google Scholar
Published January 4, 2021 - More info
J Clin Invest. 2021;131(1):e143780. https://doi.org/10.1172/JCI143780.
© 2021 American Society for Clinical Investigation
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.
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