Dataset Information

Liver depot gene therapy for Pompe disease.

ABSTRACT: Gene therapy for Pompe disease has advanced to early phase clinical trials, based upon proof-of-concept data indicating that gene therapy could surpass the benefits of the current standard of care, enzyme replacement therapy (ERT). ERT requires frequent infusions of large quantities of recombinant human acid ?-glucosidase (GAA), whereas gene therapy involves a single infusion of a vector that stably transduces tissues to continuously produce GAA. Liver-specific expression of GAA with an adeno-associated virus (AAV) vector established stable GAA secretion from the liver accompanied by receptor-mediated uptake of GAA, which corrected the deficiency of GAA and cleared the majority of accumulated glycogen in the heart and skeletal muscle. Liver depot gene therapy was equivalent to ERT at a dose of the AAV vector that could be administered in an early phase clinical trial. Furthermore, high-level expression of GAA has decreased glycogen stored in the brain. A unique advantage of liver-specific expression stems from the induction of immune tolerance to GAA following AAV vector administration, thereby suppressing anti-GAA antibodies that otherwise interfere with efficacy. A Phase I clinical trial of AAV vector-mediated liver depot gene therapy has been initiated based upon promising preclinical data (NCT03533673). Overall, gene therapy promises to address limits of currently available ERT, if clinical translation currently underway is successful.

SUBMITTER: Kishnani PS

PROVIDER: S-EPMC6642935 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Liver depot gene therapy for Pompe disease.

Kishnani Priya S PS Koeberl Dwight D DD

Annals of translational medicine 20190701 13

Gene therapy for Pompe disease has advanced to early phase clinical trials, based upon proof-of-concept data indicating that gene therapy could surpass the benefits of the current standard of care, enzyme replacement therapy (ERT). ERT requires frequent infusions of large quantities of recombinant human acid α-glucosidase (GAA), whereas gene therapy involves a single infusion of a vector that stably transduces tissues to continuously produce GAA. Liver-specific expression of GAA with an adeno-as ...[more]

PMID: 31392200

Similar Datasets

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

Liver depot gene therapy for Pompe disease.

Publications

Liver depot gene therapy for Pompe disease.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets