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.

Figure 1.

Histological evidence for neuronal glycogen accumulation in the spinal ventral horn of Pompe mouse model. Spinal tissues were harvested from 12-months-old Gaa^−/− mice. (A) This panel shows an example of paraffin-embedded tissue (10 µm sections) stained with the periodic acid schiff (PAS) method. The example is from the thoracic spinal cord and shows robust neuronal PAS staining (pink color), indicative of glycogen accumulation, throughout the ventral horn. The arrow indicates a large motoneuron with positive PAS stain. (B) This panel provides an example from another Gaa^−/− mouse in which tissue was plastic-embedded, cut at 2 µm and stained with toluidine blue. The neuron indicated by the arrow is located in the C4 ventral horn. Note the extensive accumulation of droplets in the cytoplasm with no accumulation in the nucleus. Scale bars indicate 100 (A) and 20 µm (B).

Figure 2.

Timeline of phase I/II clinical trial for Pompe disease. Following subject enrollment, a period of inspiratory muscle strength training is started prior to study agent dosing. Enzyme replacement therapy is continued throughout the study. Safety and exploratory efficacy endpoints are assessed for 1 year.

Figure 3.

Development of gene therapy for Pompe disease. The mouse model for the Pompe disease was developed at the same time as in vitro gene transfer studies were established and has been invaluable in working towards the current clinical studies.