Phase I/II Trial of Adeno-Associated Virus–Mediated Alpha-Glucosidase Gene Therapy to the Diaphragm for Chronic Respiratory Failure in Pompe Disease: Initial Safety and Ventilatory Outcomes

Abstract

Pompe disease is an inherited neuromuscular disease caused by deficiency of lysosomal acid alpha-glucosidase (GAA) leading to glycogen accumulation in muscle and motoneurons. Cardiopulmonary failure in infancy leads to early mortality, and GAA enzyme replacement therapy (ERT) results in improved survival, reduction of cardiac hypertrophy, and developmental gains. However, many children have progressive ventilatory insufficiency and need additional support. Preclinical work shows that gene transfer restores phrenic neural activity and corrects ventilatory deficits. Here we present 180-day safety and ventilatory outcomes for five ventilatordependent children in a phase I/II clinical trial of AAV-mediated GAA gene therapy (rAAV1-hGAA) following intradiaphragmatic delivery. We assessed whether rAAV1-hGAA results in acceptable safety outcomes and detectable functional changes, using general safety measures, immunological studies, and pulmonary functional testing. All subjects required chronic, full-time mechanical ventilation because of respiratory failure that was unresponsive to both ERT and preoperative muscle-conditioning exercises. After receiving a dose of either 1 · 10 12 vg (n = 3) or 5 · 10 12 vg (n = 2) of rAAV1-hGAA, the subjects' unassisted tidal volume was significantly larger (median [interquartile range] 28.8% increase [15.2-35.2], p < 0.05). Further, most patients tolerated appreciably longer periods of unassisted breathing (425% increase , p = 0.08). Gene transfer did not improve maximal inspiratory pressure. Expected levels of circulating antibodies and no T-cell-mediated immune responses to the vector (capsids) were observed. One subject demonstrated a slight increase in anti-GAA antibody that was not considered clinically significant. These results indicate that rAAV1-hGAA was safe and may lead to modest improvements in volitional ventilatory performance measures. Evaluation of the next five patients will determine whether earlier intervention can further enhance the functional benefit.

Stimulation of Respiratory Motor Output and Ventilation in a Murine Model of Pompe Disease by Ampakines

“…1,3,7,18). Several independent groups have concluded that neuropathology has a significant impact on motor function (8,49,54), but no current therapies are aimed at improving the efferent neural regulation of the respiratory muscles (although a gene therapy clinical trial is in progress [55]). In the context of the current results, it must be emphasized that rigorously controlled in vitro and in vivo experiments indicate that CX717 robustly increases respiratory activity when respiratory neuromotor activity is suppressed, but has minimal impact under conditions of "normal" respiratory motor activity (14,20,47).…”

Delivery of Recombinant Adeno-Associated Virus Vectors to Rat Diaphragm Muscle via Direct Intramuscular Injection

“…Currently, there are ongoing and completed clinical trials using rAAV as a therapeutic tool to treat diseases affecting skeletal muscle ( Mendell et al, 2009( Mendell et al, , 2010Bowles et al, 2012). For example, work with rAAV in animal models has led to the development of a gene therapy strategy for Pompe disease, which has resulted in a clinical trial of rAAV-mediated gene-based therapy for this disease (ClinicalTrials.gov Identifier: NCT00976352) Pacak and Byrne, 2011;Smith et al, 2013).…”

Profile of alglucosidase alfa in the treatment of Pompe disease: safety, efficacy, and patient acceptability

“…79 First clinical trials of gene transfer treatment in five ventilator-dependent Pompe patients demonstrated acceptable safety outcomes and longer periods of unassisted breathing. 80,81 Genome editing via CRISPR/Cas9 82 is another revolutionary approach that might tremendously change the therapeutic options for Pompe patients by modulating disease-causing alleles. However, this approach is yet far away from clinical trials.…”