Pompe disease gene therapy

Abstract

Pompe disease is an autosomal recessive metabolic myopathy caused by the deficiency of the lysosomal enzyme acid alpha-glucosidase and results in cellular lysosomal and cytoplasmic glycogen accumulation. A wide spectrum of disease exists from hypotonia and severe cardiac hypertrophy in the first few months of life due to severe mutations to a milder form with the onset of symptoms in adulthood. In either condition, the involvement of several systems leads to progressive weakness and disability. In early-onset severe cases, the natural history is characteristically cardiorespiratory failure and death in the first year of life. Since the advent of enzyme replacement therapy (ERT), the clinical outcomes have improved. However, it has become apparent that a new natural history is being defined in which some patients have substantial improvement following ERT, while others develop chronic disability reminiscent of the late-onset disease. In order to improve on the current clinical outcomes in Pompe patients with diminished clinical response to ERT, we sought to address the cause and potential for the treatment of disease manifestations which are not amenable to ERT. In this review, we will focus on the preclinical studies that are relevant to the development of a gene therapy strategy for Pompe disease, and have led to the first clinical trial of recombinant adeno-associated virus-mediated gene-based therapy for Pompe disease. We will cover the preliminary laboratory studies and rationale for a clinical trial, which is based on the treatment of the high rate of respiratory failure in the early-onset patients receiving ERT.

Preclinical Toxicology and Biodistribution Studies of Recombinant Adeno-Associated Virus 1 Human Acid α-Glucosidase

“…There are a broad range of clinical phenotypes that present at different ages that correlate to the amount of residual GAA activity (Raben et al, 2002). The most severe form, classic infantile onset Pompe disease, most often results from a null or severe missense mutation resulting in complete or nearcomplete lack of GAA (Byrne et al, 2011). Patients with this form of the disease present clinical symptoms within the first few months of life that include rapidly progressing skeletal muscle weakness, cardiomyopathy, and decline in ventilator function.…”

Profile of alglucosidase alfa in the treatment of Pompe disease: safety, efficacy, and patient acceptability

“…73 Promising future therapies also involve injection of recombinant adeno-associated virus vectors, as this therapy has been demonstrated to augment cardiac, respiratory, and motorneuron function in GAA −/− knockout mice. [74][75][76][77][78] Importantly, the degree of restoration once again seems to depend on the severity of disease. Therefore, an early therapy appears to be the most effective.…”

Gene Therapy Approaches for Lysosomal Storage Disease: Next-Generation Treatment

“…Respiratory insufficiency is one of the primary complications in Pompe disease and long-term evaluation of patients receiving ERT has revealed progressive respiratory dysfunction that may partially be attributed to the lack of correction of the neural components of respiration (Byrne et al, 2011). As mentioned previously, preclinical studies showed that direct administration of rAAV1 to diaphragms of Pompe mice could lead to improvement in diaphragm contractile strength and ventilatory function.…”

“…Strategies such as limiting expression to target tissues and avoiding expression in undesirable nontarget cells such as antigen-presenting cells by use of tissue-specific promoters have been shown to avoid provocation of a strong immune response. Interestingly, from studies investigating targeted gene expression, it was found that rAAV-mediated hepatic expression could lead to product-specific immune tolerance partially via induction of regulatory T cells (Ponder and Haskins, 2007;LoDuca et al, 2009;Nayak et al, 2009;Byrne et al, 2011;Zhang et al, 2012).…”