Pompe disease is caused by deficiency of acid α-glucosidase (GAA), resulting in glycogen accumulation in various tissues, including cardiac and skeletal muscles and the central nervous system (CNS). Enzyme replacement therapy (ERT) improves cardiac, motor, and respiratory functions but is limited by poor cellular uptake and its inability to cross the blood-brain barrier. Previously, we showed that hematopoietic stem cell (HSPC)-mediated lentiviral gene therapy (LVGT) with codon-optimized GAA (LV-GAAco) caused glycogen reduction in heart, skeletal muscles, and partially in the brain at high vector copy number (VCN). Here, we fused insulin-like growth factor 2 (IGF2) to a codon-optimized version of GAA (LV-IGF2.GAAco) to improve cellular uptake by the cation-independent mannose 6-phosphate/IGF2 (CI-M6P/IGF2) receptor. In contrast to LV-GAAco, LV-IGF2.GAAco was able to completely normalize glycogen levels, pathology, and impaired autophagy at a clinically relevant VCN of 3 in heart and skeletal muscles. LV-IGF2.GAAco was particularly effective in treating the CNS, as normalization of glycogen levels and neuroinflammation was achieved at a VCN between 0.5 and 3, doses at which LV-GAAco was largely ineffective. These results identify IGF2.GAA as a candidate transgene for future clinical development of HSPC-LVGT for Pompe disease.
|Number of pages||22|
|Journal||Molecular Therapy - Methods and Clinical Development|
|Publication status||Published - 8 Dec 2022|
G. Wagemaker was involved in the concept of the study. This work was supported by the China Scholarship Council (to Q.L., file no.
201206240040), the Netherlands Organization for Health Research ZonMw (project number: 40-40300-98-07010), the Sophia Foundation (grant S18-59), Metakids (grant 2018-083), the Prinses Beatrix Spierfonds (grant W.OP20-04), and the Finding a Cure for Hunter Disease Foundation.
Publisher Copyright: © 2022 The Author(s)