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Cas9-specific immune responses compromise local and systemic AAV CRISPR therapy in multiple dystrophic canine models.

Publication ,  Journal Article
Hakim, CH; Kumar, SRP; Pérez-López, DO; Wasala, NB; Zhang, D; Yue, Y; Teixeira, J; Pan, X; Zhang, K; Million, ED; Nelson, CE; Metzger, S ...
Published in: Nature communications
November 2021

Adeno-associated virus (AAV)-mediated CRISPR-Cas9 editing holds promise to treat many diseases. The immune response to bacterial-derived Cas9 has been speculated as a hurdle for AAV-CRISPR therapy. However, immunological consequences of AAV-mediated Cas9 expression have thus far not been thoroughly investigated in large mammals. We evaluate Cas9-specific immune responses in canine models of Duchenne muscular dystrophy (DMD) following intramuscular and intravenous AAV-CRISPR therapy. Treatment results initially in robust dystrophin restoration in affected dogs but also induces muscle inflammation, and Cas9-specific humoral and cytotoxic T-lymphocyte (CTL) responses that are not prevented by the muscle-specific promoter and transient prednisolone immune suppression. In normal dogs, AAV-mediated Cas9 expression induces similar, though milder, immune responses. In contrast, other therapeutic (micro-dystrophin and SERCA2a) and reporter (alkaline phosphatase, AP) vectors result in persistent expression without inducing muscle inflammation. Our results suggest Cas9 immunity may represent a critical barrier for AAV-CRISPR therapy in large mammals.

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Published In

Nature communications

DOI

EISSN

2041-1723

ISSN

2041-1723

Publication Date

November 2021

Volume

12

Issue

1

Start / End Page

6769

Related Subject Headings

  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Muscular Dystrophy, Duchenne
  • Muscle, Skeletal
  • Humans
  • Genetic Vectors
  • Genetic Therapy
  • Genes, Reporter
  • Gene Editing
  • Dystrophin
  • Dogs
 

Citation

APA
Chicago
ICMJE
MLA
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Hakim, C. H., Kumar, S. R. P., Pérez-López, D. O., Wasala, N. B., Zhang, D., Yue, Y., … Duan, D. (2021). Cas9-specific immune responses compromise local and systemic AAV CRISPR therapy in multiple dystrophic canine models. Nature Communications, 12(1), 6769. https://doi.org/10.1038/s41467-021-26830-7
Hakim, Chady H., Sandeep R. P. Kumar, Dennis O. Pérez-López, Nalinda B. Wasala, Dong Zhang, Yongping Yue, James Teixeira, et al. “Cas9-specific immune responses compromise local and systemic AAV CRISPR therapy in multiple dystrophic canine models.Nature Communications 12, no. 1 (November 2021): 6769. https://doi.org/10.1038/s41467-021-26830-7.
Hakim CH, Kumar SRP, Pérez-López DO, Wasala NB, Zhang D, Yue Y, et al. Cas9-specific immune responses compromise local and systemic AAV CRISPR therapy in multiple dystrophic canine models. Nature communications. 2021 Nov;12(1):6769.
Hakim, Chady H., et al. “Cas9-specific immune responses compromise local and systemic AAV CRISPR therapy in multiple dystrophic canine models.Nature Communications, vol. 12, no. 1, Nov. 2021, p. 6769. Epmc, doi:10.1038/s41467-021-26830-7.
Hakim CH, Kumar SRP, Pérez-López DO, Wasala NB, Zhang D, Yue Y, Teixeira J, Pan X, Zhang K, Million ED, Nelson CE, Metzger S, Han J, Louderman JA, Schmidt F, Feng F, Grimm D, Smith BF, Yao G, Yang NN, Gersbach CA, Chen S-J, Herzog RW, Duan D. Cas9-specific immune responses compromise local and systemic AAV CRISPR therapy in multiple dystrophic canine models. Nature communications. 2021 Nov;12(1):6769.

Published In

Nature communications

DOI

EISSN

2041-1723

ISSN

2041-1723

Publication Date

November 2021

Volume

12

Issue

1

Start / End Page

6769

Related Subject Headings

  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Muscular Dystrophy, Duchenne
  • Muscle, Skeletal
  • Humans
  • Genetic Vectors
  • Genetic Therapy
  • Genes, Reporter
  • Gene Editing
  • Dystrophin
  • Dogs