Pompe disease gene therapy: neural manifestations require consideration of CNS directed therapy

Abstract

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.

Keywords: Pompe disease; gene therapy; neuropathology.

Figure 1

Lumbar spinal cord sections from an adult dog with early onset Pompe disease (A) and an adult human with late-onset Pompe disease (B). Tissues were paraffin embedded, sectioned at 7 µm, slide mounted and stained with Periodic acid-Schiff (PAS) to recognize glycogen (pink) or with hematoxylin and eosin (H&E). Panel A shows canine cord from an 8-month-old dos who was euthanized due to progression of neurological findings. Prominent PAS stating is evident in motor neurons throughout the ventral (anterior) horn. Many of these cells show the prototypical “ballooning” appearance associated with motor neuron histopathology in lysosomal storage diseases. The tissues in Panel B are from a 55-year-old patient with late-onset Pompe disease who succumbed to respiratory failure and neurological decline. Similar to the canine cord, PAS-positive staining is prominent in neurons throughout the ventral horn, including motor neurons. The scale bars indicate 2 mm on whole tissue sections and 50 µm on inset panels.