Advancements in AAV-mediated Gene Therapy for Pompe Disease

Abstract

Pompe disease (glycogen storage disease type II) is caused by mutations in acid ␣-glucosidase (GAA) resulting in lysosomal pathology and impairment of the muscular and cardio-pulmonary systems. Enzyme replacement therapy (ERT), the only approved therapy for Pompe disease, improves muscle function by reducing glycogen accumulation but this approach entails several limitations including a short drug half-life and an antibody response that results in reduced efficacy. To address these limitations, new treatments such as gene therapy are under development to increase the intrinsic ability of the affected cells to produce GAA. Key components to gene therapy strategies include the choice of vector, promoter, and the route of administration. The efficacy of gene therapy depends on the ability of the vector to drive gene expression in the target tissue and also on the recipient's immune tolerance to the transgene protein. In this review, we discuss the preclinical and clinical studies that are paving the way for the development of a gene therapy strategy for patients with early and late onset Pompe disease as well as some of the challenges for advancing gene therapy.

Lentiviral Hematopoietic Stem Cell Gene Therapy Rescues Clinical Phenotypes in a Murine Model of Pompe Disease

“…Several studies have used adeno-associated viruses (AAVs) as a gene therapy delivery system to target via local or systemic administration specific tissues such as skeletal muscles, liver, and CNS. 7 , 15 , 16 AVV-mediated gene therapy can trigger antibody or cell-mediated immune responses to transgene or viral capsid, 16 , 17 , 18 , 19 , 20 as has been observed in clinical trials for hemophilia B 21 using AAV, but liver-directed transgene expression has been shown in pre-clinical studies 22 to potentially overcome this safety concern by induction of immune tolerance. Although AVV-mediated gene therapy remains a promising treatment, the episomal nature of viral persistence results in a dilution effect in replicating cells such as hepatocytes, particularly in younger patients, and thereby increasing safety concerns would arise for multiple dosages in those patients.…”

“…Although AVV-mediated gene therapy remains a promising treatment, the episomal nature of viral persistence results in a dilution effect in replicating cells such as hepatocytes, particularly in younger patients, and thereby increasing safety concerns would arise for multiple dosages in those patients. 18 , 22 , 23 …”

A Newborn with Infantile-Onset Pompe Disease Improving after Administration of Enzyme Replacement Therapy: Case Report

“…35 In addition, gene therapy by adeno-associated viruses is very promising. [36][37][38] In conclusion, a high index of suspicion for PD is warranted in neonates presenting with hypertrophic cardiomyopathy, muscular hypotonia, and respiratory distress. Early diagnosis is of great importance in terms of early ERT initiation.…”

Pompe Disease: New Developments in an Old Lysosomal Storage Disorder

“…Over the past years, the field has witnessed the explosion of gene therapy studies testing different types of vectors, various promoters, numerous elements of the transgene expression cassette, and routes of delivery in preclinical setting. These studies are discussed in several recent reviews [102,[122][123][124][125]. Here, we focused on already initiated and planned gene-therapy-based clinical trials using nonpathogenic adeno-associated virus (AAV) as a vector (Table 1).…”