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Gene therapy for Pompe disease: the time is now.

Abstract

Pompe disease (PD) is caused by the deficiency of the lysosomal enzyme acid α-glucosidase (GAA), resulting in systemic pathological glycogen accumulation. PD can present with cardiac, skeletal muscle, and central nervous system (CNS) manifestations, as a continuum of phenotypes among two main forms: classical infantile-onset PD (IOPD) and late-onset PD (LOPD). IOPD is caused by severe GAA deficiency and presents at birth with cardiac hypertrophy, muscle hypotonia and severe respiratory impairment, leading to premature death, if not treated. LOPD is characterized by levels of residual GAA activity up to ~20% of normal and presents both in children and adults with a varied severity of muscle weakness, motor and respiratory deficit. Enzyme replacement therapy (ERT), based on repeated intravenous infusions of recombinant human GAA (rhGAA), represents the only available treatment for PD. Upon more than 10 years from its launch, it is becoming evident that ERT can extend the lifespan of IOPD and stabilize disease progression in LOPD, however it does not represent a cure for PD. The limited uptake of the enzyme in key affected tissues and the high immunogenicity of rhGAA are some of the hurdles that limit ERT efficacy. GAA gene transfer with adeno-associated virus (AAV) vectors has been shown to reduce glycogen storage and improve the PD phenotype in pre-clinical studies following different approaches. Here, we will present an overview of the different gene therapy approaches for PD, focusing on in vivo gene transfer with AAV vectors and discussing the potential opportunities and challenges in developing safe and effective gene therapies for the disease. Based on emerging safety and efficacy data from clinical trials for other protein deficiencies, in vivo gene therapy with AAV vectors appears to have the potential to provide a therapeutically relevant, stable source of GAA enzyme, which could be highly beneficial in PD.

Authors+Show Affiliations

Stanford University, 6429 , 265, Campus drive , Stanford, California, United States , 94305-6104 ; lina.colella@gmail.com.Genethon, 52832, Evry, Île-de-France, France. Spark therapeutics, Philadelphia, United States ; federico.mingozzi@sparktx.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31298581

Citation

Colella, Pasqualina, and Federico Mingozzi. "Gene Therapy for Pompe Disease: the Time Is Now." Human Gene Therapy, 2019.
Colella P, Mingozzi F. Gene therapy for Pompe disease: the time is now. Hum Gene Ther. 2019.
Colella, P., & Mingozzi, F. (2019). Gene therapy for Pompe disease: the time is now. Human Gene Therapy, doi:10.1089/hum.2019.109.
Colella P, Mingozzi F. Gene Therapy for Pompe Disease: the Time Is Now. Hum Gene Ther. 2019 Jul 12; PubMed PMID: 31298581.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Gene therapy for Pompe disease: the time is now. AU - Colella,Pasqualina, AU - Mingozzi,Federico, Y1 - 2019/07/12/ PY - 2019/7/13/entrez JF - Human gene therapy JO - Hum. Gene Ther. N2 - Pompe disease (PD) is caused by the deficiency of the lysosomal enzyme acid α-glucosidase (GAA), resulting in systemic pathological glycogen accumulation. PD can present with cardiac, skeletal muscle, and central nervous system (CNS) manifestations, as a continuum of phenotypes among two main forms: classical infantile-onset PD (IOPD) and late-onset PD (LOPD). IOPD is caused by severe GAA deficiency and presents at birth with cardiac hypertrophy, muscle hypotonia and severe respiratory impairment, leading to premature death, if not treated. LOPD is characterized by levels of residual GAA activity up to ~20% of normal and presents both in children and adults with a varied severity of muscle weakness, motor and respiratory deficit. Enzyme replacement therapy (ERT), based on repeated intravenous infusions of recombinant human GAA (rhGAA), represents the only available treatment for PD. Upon more than 10 years from its launch, it is becoming evident that ERT can extend the lifespan of IOPD and stabilize disease progression in LOPD, however it does not represent a cure for PD. The limited uptake of the enzyme in key affected tissues and the high immunogenicity of rhGAA are some of the hurdles that limit ERT efficacy. GAA gene transfer with adeno-associated virus (AAV) vectors has been shown to reduce glycogen storage and improve the PD phenotype in pre-clinical studies following different approaches. Here, we will present an overview of the different gene therapy approaches for PD, focusing on in vivo gene transfer with AAV vectors and discussing the potential opportunities and challenges in developing safe and effective gene therapies for the disease. Based on emerging safety and efficacy data from clinical trials for other protein deficiencies, in vivo gene therapy with AAV vectors appears to have the potential to provide a therapeutically relevant, stable source of GAA enzyme, which could be highly beneficial in PD. SN - 1557-7422 UR - https://www.unboundmedicine.com/medline/citation/31298581/Gene_therapy_for_Pompe_disease:_the_time_is_now L2 - https://www.liebertpub.com/doi/full/10.1089/hum.2019.109?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -