This study describes the results of the first in human trial of diaphragmatic gene therapy (AAV1-CMV-GAA) to treat respiratory and neural dysfunction in early-onset Pompe disease. The primary objective was to assess the safety of rAAV1-CMV-hGAA vector delivered to the diaphragm muscle of Pompe disease subjects with ventilatory insufficiency. Safety was assessed by measurement of change in serum chemistries and hematology, urinalysis, and immune response to GAA and AAV as well as change in level of health. The data demonstrate that the AAV treatment was safe and there were no adverse events related to the study agent. Adverse events related to the study procedure were observed in subjects with lower baseline neuromuscular function. All adverse events were resolved before the end of the study, except for one severe adverse event determined to be not related to either the study agent or the study procedure. In addition, the investigators observed an anti-capsid and anti-transgene antibody response in all subjects that received rAAV1-CMV-hGAA, except for subjects that received concomitant immunomodulation to manage reaction to enzyme replacement therapy, as per their standard of care. This observation is significant for future gene therapy studies and serves to establish a clinically relevant approach to blocking immune responses to both the AAV capsid protein and transgene product.
