Synergism of dual AAV gene therapy and rapamycin rescues GSDIII phenotype in muscle and liver

JCI Insight. 2024 May 16;9(11):e172614. doi: 10.1172/jci.insight.172614.


Glycogen storage disease type III (GSDIII) is a rare metabolic disorder due to glycogen debranching enzyme (GDE) deficiency. Reduced GDE activity leads to pathological glycogen accumulation responsible for impaired hepatic metabolism and muscle weakness. To date, there is no curative treatment for GSDIII. We previously reported that 2 distinct dual AAV vectors encoding for GDE were needed to correct liver and muscle in a GSDIII mouse model. Here, we evaluated the efficacy of rapamycin in combination with AAV gene therapy. Simultaneous treatment with rapamycin and a potentially novel dual AAV vector expressing GDE in the liver and muscle resulted in a synergic effect demonstrated at biochemical and functional levels. Transcriptomic analysis confirmed synergy and suggested a putative mechanism based on the correction of lysosomal impairment. In GSDIII mice livers, dual AAV gene therapy combined with rapamycin reduced the effect of the immune response to AAV observed in this disease model. These data provide proof of concept of an approach exploiting the combination of gene therapy and rapamycin to improve efficacy and safety and to support clinical translation.

Keywords: Autophagy; Gene therapy; Skeletal muscle; Therapeutics.

MeSH terms

  • Animals
  • Dependovirus* / genetics
  • Disease Models, Animal*
  • Genetic Therapy* / methods
  • Genetic Vectors* / administration & dosage
  • Genetic Vectors* / genetics
  • Glycogen Debranching Enzyme System / genetics
  • Glycogen Debranching Enzyme System / metabolism
  • Humans
  • Liver* / metabolism
  • Male
  • Mice
  • Muscle, Skeletal / metabolism
  • Phenotype
  • Sirolimus* / pharmacology
  • Sirolimus* / therapeutic use


  • Sirolimus
  • Glycogen Debranching Enzyme System