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Review
. 2019 Aug:342:103737.
doi: 10.1016/j.cellimm.2017.12.011. Epub 2017 Dec 29.

Immunomodulatory, liver depot gene therapy for Pompe disease

J E Bond  1 , P S Kishnani  2 , D D Koeberl  3
Affiliations
Review

Immunomodulatory, liver depot gene therapy for Pompe disease

J E Bond et al. Cell Immunol. 2019 Aug.

Abstract

Pompe disease is caused by mutations in acid alpha glucosidase (GAA) that causes accumulation of lysosomal glycogen affecting the heart and skeletal muscles, and can be fatal. Enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA) improves muscle function by reducing glycogen accumulation. Limitations of ERT include a short half-life and the formation of antibodies that result in reduced efficacy. By harnessing the immune tolerance induction properties of the liver, liver-targeted gene delivery (with an adeno-associated virus vector containing a liver specific promoter), suppresses immunity against the GAA introduced by gene therapy. This induces immune tolerance to rhGAA by activating regulatory T cells and simultaneously, corrects GAA deficiency. Potentially, liver-targeted gene therapy can be performed once with lasting effects, by administering a relatively low dose of an adeno-associated virus type 8 vector to replace and induce immune tolerance to GAA.

Keywords: Acid alpha-glucosidase; Antibody response; Enzyme replacement therapy; Gene therapy; Glycogen storage disease; Immune tolerance; Pompe disease.

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Conflict of interest statement

Disclosure/Conflict of interest: DDK has developed the technology that is being used in the study. If the technology is commercially successful in the future, the developers and Duke University may benefit financially. DDK has received research/grant support from Sanofi Genzyme Corporation in the past, and rhGAA for these studies was supplied by Sanofi Genzyme.

Figures

Figure 1
Figure 1. Immunomodulatory Gene Therapy for Pompe Disease
Liver depot with AAV2/8-LSPhGAA. Treatment with rAAV8 converts the liver to a depot for continuous secretion of GAA, correcting GAA deficiency in the heart and skeletal muscle. Liver expression induces immune tolerance to rhGAA by reducing antibody formation through suppression by regulatory T cells.
See this image and copyright information in PMC

References

    1. Elliott S, Buroker N, Cournoyer JJ, et al. Pilot study of newborn screening for six lysosomal storage diseases using Tandem Mass Spectrometry. Mol Genet Metab. 2016;118:304–9. - PMC - PubMed
    1. Hopkins PV, Campbell C, Klug T, et al. Lysosomal storage disorder screening implementation: findings from the first six months of full population pilot testing in Missouri. J Pediatr. 2015;166:172–177. - PubMed
    1. Kishnani PS, Hwu WL, Mandel H, et al. A retrospective, multinational, multicenter study on the natural history of infantile-onset Pompe disease. J Pediatr. 2006;148:671–676. - PubMed
    1. van Gelder CM, Poelman E, Plug I, et al. Effects of a higher dose of alglucosidase alfa on ventilator-free survival and motor outcome in classic infantile Pompe disease: an open-label single-center study. J Inherit Metab Dis. 2016;39:383–390. - PMC - PubMed
    1. Case LE, Bjartmar C, Morgan C, et al. Safety and efficacy of alternative alglucosidase alfa regimens in Pompe disease. Neuromuscul Disord. 2015;25:321–332. - PubMed

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