Neonatal gene therapy restores breathing in a rat model of Pompe disease

Abstract

Pompe disease is a neuromuscular disorder resulting from mutations in the gene for acid a-glucosidase (GAA) – an enzyme necessary to degrade lysosomal glycogen. Early-onset disease occurs in the absence of functional GAA, which leads to cardiorespiratory failure early in life. Late-onset disease is associated with reduced GAA activity and gradual respiratory failure with preserved cardiac function. The standard of care – intravenous enzyme replacement therapy (ERT) using recombinant GAA does not effectively target the central nervous system, and can delay but not prevent respiratory failure. We used a Pompe rat model ( Gaa null) to test the hypothesis that a single intravenous AAV-GAA dose in neonate Pompe rats can drive persistent and widespread GAA expression and prevent respiratory decline over the lifespan. Male Gaa -/- rats received a single intravenous administration of AAV9-DES-hGAA (1x1014 vector genomes/kg; n=6), temporal vein injection) or sham injection (1xPBS; n=6) on post-natal day one. Ventilation was measured using a whole-body plethysmograph at age 3-, 6-, and 9-months. Rats treated with the gene therapy vector showed a striking increase in body mass over the duration of the study (2-way repeated measures analyses of variance, treatment effect, p<0.001). At age 9 mo, treated rats weighed 402±25 g and sham rats weighed 293±27 g. As rats progressed from 3- to 9-months age, tidal volume, minute ventilation, and the ratio of minute ventilation to CO2 production (i.e., V E /VCO 2 ) were all greater in the gene therapy treated rats as compared to sham (each of these variables showed an age x treatment interaction, all p<0.001). We conclude the neonatal gene therapy with AAV9-DES-hGAA can prevent decline in body mass and preserve breathing ability over the lifespan of a Pompe rat model. Gene therapy is a promising approach for treating Pompe disease. Funding: R01HD052682 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.