A Neuron-Specific Gene Therapy Relieves Motor Deficits in Pompe Disease Mice

Abstract

In Pompe disease, deficient lysosomal acid α-glucosidase (GAA) activity causes glycogen accumulation in the muscles, which leads to weakness, cardiomyopathy, and respiratory failure. Although glycogen accumulation also occurs in the nervous system, the burden of neurological deficits in Pompe disease remains obscure. In this study, a neuron-specific gene therapy was administered to Pompe mice through intracerebroventricular injection of a viral vector carrying a neuron-specific promoter. The results revealed that gene therapy increased GAA activity and decreased glycogen content in the brain and spinal cord but not in the muscles of Pompe mice. Gene therapy only slightly increased the muscle strength of Pompe mice but substantially improved their performance on the rotarod, a test measuring motor coordination. Gene therapy also decreased astrogliosis and increased myelination in the brain and spinal cord of Pompe mice. Therefore, a neuron-specific treatment improved the motor coordination of Pompe mice by lowering glycogen accumulation, decreasing astrogliosis, and increasing myelination. These findings indicate that neurological deficits are responsible for a significant burden in Pompe disease.

Pompe Disease: From Basic Science to Therapy

“…Neurological deficits caused by the excess glycogen accumulation in the central nervous system (CNS) and peripheral nervous system contribute to muscle dysfunction. In a series of studies using spinal, intrathecal, or intracerebroventricular delivery of AAV-GAA, neuromuscular improvement was observed, although muscle glycogen storage was not affected by the treatments [135][136][137]. Better outcomes were achieved by systemic delivery of AAV vectors of different serotypes.…”

The Respiratory Phenotype of Pompe Disease Mouse Models

“…Gaa −/− mice have reduced GAA activity in motor neurons within the 3rd-5th segment of the cervical spinal cord where phrenic motor neurons are located [52,63,64]. Furthermore, PAS+ staining, a marker for glycogen accumulation, is present throughout the cervical spinal cord of Gaa −/− mice and is most evident in the ventral grey matter, where motor neurons, including phrenic motor neurons, are located [43,48,49,64]. In fact, PAS+ staining in the spinal cord reveals progressive accumulation of glycogen in the ventral horn of the spinal cord [65].…”

Targeted delivery of acid alpha-glucosidase corrects skeletal muscle phenotypes in Pompe disease mice

“…Abnormalities in the neuromuscular junction have been linked with glycogen deposits in spinal motor neurons in mice 4 , and infantile-onset patients show secondary symptoms indicative of neural involvement 3,29 . Studies normalizing glycogen levels solely in the brain and CNS in PD mice (using AAV gene therapy) have shown correction of some neuromuscular phenotypes even in the absence of improvement in cardiac or skeletal muscle fibers, demonstrating that a full reversion of clinical phenotypes in PD ERT will require multisystem delivery 30,31 . While we and others have seen a trend or partial reduction in CNS glycogen storage (Supplementary Figure S9) 27 , it remains unknown whether this reduction will be clinically significant in PD patients.…”

“…Therefore, adding blood-brain barrier crossing functionality to neuronal lysosome targeting in a format such as a bispecific antibody may be able to improve overall efficacy 32,33 . Alternatively, AAV may be delivered via an intrathecal or intracerebroventricular route as well as intravenously to treat both the CNS and skeletal muscle 29,30 .…”