AAV9-mediated GAA gene therapy following enzyme replacement therapy discontinuation in children with infantile-onset Pompe disease

Background While our previous research showed that a single infusion of recombinant AAV9-mediated GAA gene therapy enabled infants (<1 year) with infantile-onset Pompe disease (IOPD) and minimal prior enzyme replacement therapy (ERT) to remain ventilator- and ERT-free for at least one year, it was unknown whether the same benefits could be sustained in older children with IOPD with prolonged, high-dose ERT exposure after treatment cessation. Methods In this investigator-initiated, single-arm trial (ChiCTR2200065664), six children with IOPD aged 12.5–50.8 months—all having previously received 10–98 cycles of ERT—were enrolled and administered a single intravenous infusion of AAV9-mediated gene therapy. Over a 12-month period, the following outcomes were evaluated: primary efficacy endpoints (gross motor function, and cardiac structure and function); secondary efficacy endpoints (ventilator-free survival, and the proportion of patients who showed improvement at the end of the trial); exploratory endpoints (IOPD-related skeletal muscle pathological changes); safety and tolerability endpoints; and immunogenicity assessment endpoints. Findings The intervention was generally well tolerated, with a low incidence of grade ≥3 adverse events (2.31 events per person-time). All six patients remained ventilator-free over the one-year observation period (one patient required transient ventilatory support for pneumonia). However, lung function and cardiac structure showed no further improvement after gene therapy. All children (patient 4 was not documented due to early withdrawal from the study) maintained sustained growth and development throughout follow-up, and overall quality of life showed a trend of improvement (PedsQL 3.0 NMM). During the study period, patient 1 achieved standing with assistance and crawling; patient 2 achieved standing and walking without assistance; and patient 3 achieved walking and sitting without assistance. Muscle biopsies from the three patients revealed relatively high GAA enzyme activity and reduced glycogen accumulation. Interpretation These preliminary findings suggest that AAV9-mediated GAA gene therapy may reduce reliance on ERT and is associated with improvements in muscle histopathology among biopsied participants. Funding 2023YFC3403300; Z231100004823022.