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Progress and challenges of gene therapy for Pompe disease.

ABSTRACT: Pompe disease (PD) is a monogenic disorder caused by mutations in the acid alpha-glucosidase gene (Gaa). GAA is a lysosomal enzyme essential for the degradation of glycogen. Deficiency of GAA results in a severe, systemic disorder that, in its most severe form, can be fatal. About a decade ago, the prognosis of PD has changed dramatically with the marketing authorization of an enzyme replacement therapy (ERT) based on recombinant GAA. Despite the breakthrough nature of ERT, long-term follow-up of both infantile and late-onset Pompe disease patients (IOPD and LOPD, respectively), revealed several limitations of the approach. In recent years several investigational therapies for PD have entered preclinical and clinical development, with a few next generation ERTs entering late-stage clinical development. Gene therapy holds the potential to change dramatically the way we treat PD, based on the ability to express the Gaa gene long-term, ideally driving enhanced therapeutic efficacy compared to ERT. Several gene therapy approaches to PD have been tested in preclinical animal models, with a handful of early phase clinical trials started or about to start. The complexity of PD and of the endpoints used to measure efficacy of investigational treatments remains a challenge, however the hope is for a future with more therapeutic options for both IOPD and LOPD patients.

SUBMITTER: Ronzitti G

PROVIDER: S-EPMC6642941 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Progress and challenges of gene therapy for Pompe disease.

Ronzitti Giuseppe G Collaud Fanny F Laforet Pascal P Mingozzi Federico F

Annals of translational medicine 20190701 13

Pompe disease (PD) is a monogenic disorder caused by mutations in the acid alpha-glucosidase gene (<i>Gaa</i>). GAA is a lysosomal enzyme essential for the degradation of glycogen. Deficiency of GAA results in a severe, systemic disorder that, in its most severe form, can be fatal. About a decade ago, the prognosis of PD has changed dramatically with the marketing authorization of an enzyme replacement therapy (ERT) based on recombinant GAA. Despite the breakthrough nature of ERT, long-term foll ...[more]

PMID: 31392199

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Project description:Pompe disease is a neuromuscular disease caused by a deficiency of the lysosomal enzyme acid alpha-glucosidase leading to lysosomal and cytoplasmic glycogen accumulation in neurons and striated muscle. In the decade since availability of first-generation enzyme replacement therapy (ERT) a better understanding of the clinical spectrum of disease has emerged. The most severe form of early onset disease is typically identified with symptoms in the first year of life, known as infantile-onset Pompe disease (IOPD). Infants are described at floppy babies with cardiac hypertrophy in the first few months of life. A milder form with late onset (LOPD) of symptoms is mostly free of cardiac involvement with slower rate of progression. Glycogen accumulation in the CNS and skeletal muscle is observed in both IOPD and LOPD. In both circumstances, multi-system disease (principally motoneuron and myopathy) leads to progressive weakness with associated respiratory and feeding difficulty. In IOPD the untreated natural history leads to cardiorespiratory failure and death in the first year of life. In the current era of ERT clinical outcomes are improved, yet, many patients have an incomplete response and a substantial unmet need remains. Since the neurological manifestations of the disease are not amenable to peripheral enzyme replacement, we set out to better understand the pathophysiology and potential for treatment of disease manifestations using adeno-associated virus (AAV)-mediated gene transfer, with the first clinical gene therapy studies initiated by our group in 2006. This review focuses on the preclinical studies and clinical study findings which are pertinent to the development of a comprehensive gene therapy strategy for both IOPD and LOPD. Given the advent of newborn screening, a significant focus of our recent work has been to establish the basis for repeat administration of AAV vectors to enhance neuromuscular therapeutic efficacy over the life span.

Dataset Information

Progress and challenges of gene therapy for Pompe disease.

Publications

Progress and challenges of gene therapy for Pompe disease.

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