Inspiratory muscle conditioning exercise and diaphragm gene therapy in Pompe disease: Clinical evidence of respiratory plasticity

Abstract

Pompe disease is an inherited disorder due to a mutation in the gene that encodes acid α-glucosidase (GAA). Children with infantile-onset Pompe disease develop progressive hypotonic weakness and cardiopulmonary insufficiency that may eventually require mechanical ventilation (MV). Our team conducted a first in human trial of diaphragmatic gene therapy (AAV1-CMV-GAA) to treat respiratory neural dysfunction in infantile-onset Pompe. Subjects (aged 2-15 years, full-time MV: n=5, partial/no MV: n=4) underwent a period of preoperative inspiratory muscle conditioning exercise. The change in respiratory function after exercise alone was compared to the change in function after intramuscular delivery of AAV1-CMV-GAA to the diaphragm with continued exercise. Since AAV-mediated gene therapy can reach phrenic motoneurons via retrograde transduction, we hypothesized that AAV1-CMV-GAA would improve dynamic respiratory motor function to a greater degree than exercise alone. Dependent measures were maximal inspiratory pressure (MIP), respiratory responses to inspiratory threshold loads (load compensation: LC), and physical evidence of diaphragm activity (descent on MRI, EMG activity). Exercise alone did not change function. After AAV1-CMV-GAA, MIP was unchanged. Flow and volume LC responses increased after dosing (p<0.05 to p<0.005), but only in the subjects with partial/no MV use. Changes in LC tended to occur on or after 180 days. At Day 180, the four subjects with MRI evidence of diaphragm descent had greater maximal voluntary ventilation (p<0.05) and tended to be younger, stronger, and use fewer hours of daily MV. In conclusion, combined AAV1-CMV-GAA and exercise training conferred benefits to dynamic motor function of the diaphragm. Children with a higher baseline neuromuscular function may have greater potential for functional gains.

Chemogenetic enhancement of functional recovery after a sciatic nerve injury

“…Improvements in viral vector delivery and subsequent application of DREADDs may hold a significant therapeutic potential (Saloman et al ., ; Whissell et al ., ) for individuals with peripheral nerve injury. Although many more studies need to be conducted before the clinical use of viral vectors (Castle et al ., ) and designer receptors, the use of gene therapy to treat individuals is not beyond the realm of possibility (Smith et al ., ).…”

Pompe Disease: From Basic Science to Therapy

“…Based on these preclinical studies, the first-in-human trial of diaphragmatic gene therapy (AAV1-CMV-GAA) was conducted in five children with IOPD who required assisted ventilation prior to the study. This trial has been recently completed [145][146][147][148]. The study demonstrated the safety of the AAV treatment, but the clinical outcome was minimal: no improvements in muscle function or dissemination of the GAA transgene were detected outside of the injected tissue.…”

Rescue of Pompe disease in mice by AAV-mediated liver delivery of secretable acid α-glucosidase

“…A clinical trial of GAA gene transfer using AAV1 injected into the diaphragm of patients with Pompe disease has recently been completed (20, 21). The study demonstrated the safety of the approach, although the local delivery limited efficacy to the treated diaphragm muscle (20, 21). Another clinical trial is planned (ClinicalTrials.gov ID: NCT02240407) in which an AAV9 vector, carrying the GAA transgene, will be injected intramuscularly in the tibialis anterior of Pompe patients under immunosuppressive regimen (22).…”