Safety of Intradiaphragmatic Delivery of Adeno-Associated Virus-Mediated Alpha-Glucosidase (rAAV1-CMV-hGAA) Gene Therapy in Children Affected by Pompe Disease

Abstract

A first-in-human trial of diaphragmatic gene therapy (AAV1-CMV-GAA) to treat respiratory and neural dysfunction in early-onset Pompe disease was conducted. The primary objective of this study 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 not to be related to either the study agent or the study procedure. In addition, an anti-capsid and anti-transgene antibody response was observed in all subjects who received rAAV1-CMV-hGAA, except for subjects who 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.

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.…”

Extension of the Pompe mutation database by linking disease‐associated variants to clinical severity

“…If approved, other potential therapies currently under preclinical development may, depending on the predicted phenotype, be the most suitable for certain types of Pompe patients. These include AAV-mediated gene therapy directed toward the diaphragm (Corti et al, 2017) Administrative Department of Science, Technology and Innovation…”

Advancements in AAV-mediated Gene Therapy for Pompe Disease

“…In recent publications by Corti et al [144,145], circulating anti-AAV1 and anti-GAA antibodies in a group of children with Pompe disease who received bilateral intra-diaphragmatic injection of rAAV1-CMV-hGAA were studied. Three subjects receiving immunomodulation with rituximab (every 6 months) and Sirolimus (daily) to modulate immune reaction to ERT were compared to six subjects who did not receive immunomodulation.…”

“…The group that did not receive immunomodulation demonstrated a 150fold increase in anti-AAV1 titer after exposure to AAV1. However, the three subjects, who received immunomodulation had no detectable levels of anti-AAV1 or anti-GAA antibody through day 365 of the study [144,145]. In another study with a 2-year-old Canavan disease subject, immunomodulation with rituximab and sirolimus prevented formation of anti-AAV9 antibodies and prolonged the detection of AAV vector DNA in the circulation for up to 17 months [146].…”