Hepatic expression of GAA results in enhanced enzyme bioavailability in mice and non-human primates

Abstract

Pompe disease (PD) is a severe neuromuscular disorder caused by deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA). PD is currently treated with enzyme replacement therapy (ERT) with intravenous infusions of recombinant human GAA (rhGAA). Although the introduction of ERT represents a breakthrough in the management of PD, the approach suffers from several shortcomings. Here, we developed a mouse model of PD to compare the efficacy of hepatic gene transfer with adeno-associated virus (AAV) vectors expressing secretable GAA with long-term ERT. Liver expression of GAA results in enhanced pharmacokinetics and uptake of the enzyme in peripheral tissues compared to ERT. Combination of gene transfer with pharmacological chaperones boosts GAA bioavailability, resulting in improved rescue of the PD phenotype. Scale-up of hepatic gene transfer to non-human primates also successfully results in enzyme secretion in blood and uptake in key target tissues, supporting the ongoing clinical translation of the approach.

Liver-directed gene therapy corrects neurologic disease in a murine model of mucopolysaccharidosis type I-Hurler

“…For example, liver-directed AAV8 gene therapy significantly improves disease phenotypes in MPS I, MPS IVA, and Pompe disease models, including skeletal and cardiovascular damage, demonstrating the potential value of this treatment approach. [5][6][7][8] Nonetheless, because lysosomal enzymes do not effectively cross the BBB, this treatment approach is ineffective for treating central nervous system (CNS) manifestations. In addition, phase I/II gene therapy with an intracisternally administered AAV9 vector containing an IDUA expression cassette (RGX-111) is currently being tested as a strategy to directly target the CNS of individuals with MPS I (ClinicalTrials.gov: NCT03580083).…”

Gene Therapy Developments for Pompe Disease

“…The high amount of secreted GAA from the liver in non-human primates and reduced anti-GAA antibodies to the sp7-delta8-coGAA confirmed reduced immunogenicity with increased GAA activity in plasma and skeletal muscles. In a follow-up study, AAV8 secretable GAA was compared to ERT in Gaa −/− Cd4 −/− immune-compromised mice, and liver-directed gene therapy, and particularly at high dose (2 × 10 12 vg/kg) provided robust GAA activity in muscles and glycogen reduction [ 28 ]. In the CNS, GAA protein and activity were significantly increased in the spinal cord and brain, but effects on reducing glycogen in brain were less pronounced compared to the spinal cord.…”

“…After transduction of cells of interest, continuous production of therapeutic transgene product provides sustained levels in transduced cells and/or secreted levels in plasma for cross-correction in key tissues. Application of gene therapy may impact the bioavailability of therapeutic enzymes to enhance uptake and correction in key tissues compared to ERT as shown by Costa-Verdera and colleagues [ 28 ]. Horizontal dotted line represents the critical threshold to prevent Pompe disease phenotype.…”

Harnessing the liver to induce antigen-specific immune tolerance

“…However, immunogenicity of vector and transgene are still a limitation of this method, providing an obstacle to long-term transgene expression in patients [ 64 , 66 ]. In mouse models, however, immunogenicity could be avoided, when expression of the transferred gene was restricted to hepatocytes [ 67 – 70 ], once more illustrating the potential of liver tolerance.…”