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Muscle Gene Therapy pp 775–786Cite as

Muscle-Directed Gene Therapy for Alpha-1 Antitrypsin Deficiency

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Abstract

Alpha-1 antitrypsin (AAT) deficiency is a common monogenic disorder resulting in emphysema, which is currently treated with weekly infusions of protein replacement. We have reported achieving plasma wild-type (M) AAT concentrations at greater than 2% of the therapeutic level at 1 and 5 years after intramuscular (IM) administration of 6 × 1012 vg/kg of a recombinant adeno-associated virus serotype 1 (rAAV1)-AAT vector in AAT-deficient patients. This persistent expression was associated with a regulatory T cell (Treg) response to AAV1 capsid epitopes in the absence of any exogenous immune suppression. The patients also showed partial correction of functional biomarkers of AAT expression, including an increase in antineutrophil elastase capacity and a decrease in markers of neutrophil degranulation. Muscle-based gene therapy has allowed us to avoid targeting the liver, therefore preventing potential toxicity in patients where the hepatocytes are burdened with mutant AAT protein. Future muscle gene therapy will likely require dose escalation using a limb perfusion delivery method in order to obtain therapeutic serum levels of AAT while still avoiding delivery to the liver.

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Acknowledgments

This work was supported in part by grants from the NIH (P01HL131471).

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Authors and Affiliations

  1. Department of Pediatrics and Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA, USA

    Alisha M. Gruntman & Terence R. Flotte

  2. Department of Clinical Sciences, Cummings School of Veterinary Medicine, Tufts University, North Grafton, MA, USA

    Alisha M. Gruntman

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  1. Alisha M. Gruntman
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  2. Terence R. Flotte
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Correspondence to Alisha M. Gruntman .

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Editors and Affiliations

  1. Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia, MO, USA; Department of Neurology, School of Medicine, University of Missouri, Columbia, MO, USA, Department of Biomedical Sciences College of Veterinary Medicine, University of Missouri, Columbia, MO, USA; Department of Bioengineering, University of Missouri, Columbia, MO, USA

    Dongsheng Duan

  2. Department of Pediatrics Nationwide Children’s Hospital and Research Institute, Department of Neurology Nationwide Children’s Hospital and Research Institute, The Ohio State University, Columbus, OH, USA

    Jerry R. Mendell

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Gruntman, A.M., Flotte, T.R. (2019). Muscle-Directed Gene Therapy for Alpha-1 Antitrypsin Deficiency. In: Duan, D., Mendell, J. (eds) Muscle Gene Therapy. Springer, Cham. https://doi.org/10.1007/978-3-030-03095-7_45

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