Comparing two adeno-associated virus (AAV) strategies for preventing respiratory decline in Pompe disease

Pompe disease is a recessively inherited glycogen storage disease caused by a deficiency in the lysosomal enzyme acid α-glucosidase (GAA). Respiratory failure is common in Pompe disease. Data from Gaa -/- animal models and Pompe patients show that respiratory muscles and respiratory motoneurons have profound glycogen accumulation and pathology. Thus, respiratory therapies need to target the entire motor unit for optimal efficacy. The only approved treatment for Pompe disease is human recombinant GAA enzyme replacement therapy (ERT) which somewhat improves skeletal muscle function but does not cross the blood-brain barrier. Here we used a GAA null rat model of Pompe disease to compare the impact of two different AAV strategies on breathing over the Pompe lifespan. The first strategy (“Syn-GAA”) was a single dose at birth (P0) of AAV9 expressing GAA under the control of the synapsin promoter (rAAV9-Syn-H201L-coGAA at 1x10 14 vector genomes (vg)/kg). The second strategy (“Dual-AAV”) was to deliver AAV9 expressing GAA at P0, but with a liver specific promotor (LSP) (rAAV9-LSP-H201L-coGAA, 1x10 14 vg/kg). These animals then received a second AAV9 dose at age 1-month, with a desmin (Des) promoter (rAAV9-Des-H201L-coGAA, 1x10 14 vg/kg). A control Gaa -/- group received no treatment. We studied male rats, with n=5 per group. Ventilation was measured using a whole-body plethysmograph at age 6 months. Body mass was 309±39g in AAV9-Syn, 364±31g in Dual-AAV, and 275±34g in control Gaa -/- rats (p=0.005). During baseline breathing (room air), the Syn-GAA-treated rats breathed with greater tidal volumes (VT) compared to the other two groups. Thus, VT (ml/breath) was 0.68±0.09ml in Syn-GAA, 0.55±0.04 in Dual-AAV, and 0.35±0.2ml in control rats (p=0.01). Respiratory rate at baseline tended to be reduced in the Syn-GAA group (p=0.16). An acute respiratory challenge was given (7% inspired CO 2 ) to test the ability of the rats to increase breathing. The Syn-GAA-treated group had a strikingly larger response compared to the other two groups. Minute ventilation during the challenge reached 480±120 %baseline in the Syn-GAA group compared to 260±55 and 280±120% baseline in the Dual-AAV and control groups, respectively (p=0.024). These results indicate that both the Syn-GAA and Dual-AAV paradigms mitigate weight loss in the Pompe rat model. However, early (P0) treatment with Syn-GAA appears to better preserve breathing ability over the lifespan, likely due to the targeted delivery of GAA enzyme to the CNS. R01HD052682 (DDF and BJB) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.