PMID- 36284764 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20221028 IS - 2329-0501 (Print) IS - 2329-0501 (Electronic) IS - 2329-0501 (Linking) VI - 27 DP - 2022 Dec 8 TI - IGF2-tagging of GAA promotes full correction of murine Pompe disease at a clinically relevant dosage of lentiviral gene therapy. PG - 109-130 LID - 10.1016/j.omtm.2022.09.010 [doi] AB - Pompe disease is caused by deficiency of acid alpha-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. CI - (c) 2022 The Author(s). FAU - Liang, Qiushi AU - Liang Q AD - Department of Hematology and Research Laboratory of Hematology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China. AD - Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam 3015GE, the Netherlands. AD - Department of Pediatrics, Erasmus MC University Medical Center, Rotterdam 3015GE, the Netherlands. AD - Center for Lysosomal and Metabolic Diseases, Erasmus MC University Medical Center, Rotterdam 3015GE, the Netherlands. FAU - Catalano, Fabio AU - Catalano F AD - Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam 3015GE, the Netherlands. AD - Department of Pediatrics, Erasmus MC University Medical Center, Rotterdam 3015GE, the Netherlands. AD - Center for Lysosomal and Metabolic Diseases, Erasmus MC University Medical Center, Rotterdam 3015GE, the Netherlands. FAU - Vlaar, Eva C AU - Vlaar EC AD - Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam 3015GE, the Netherlands. AD - Department of Pediatrics, Erasmus MC University Medical Center, Rotterdam 3015GE, the Netherlands. AD - Center for Lysosomal and Metabolic Diseases, Erasmus MC University Medical Center, Rotterdam 3015GE, the Netherlands. FAU - Pijnenburg, Joon M AU - Pijnenburg JM AD - Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam 3015GE, the Netherlands. AD - Department of Pediatrics, Erasmus MC University Medical Center, Rotterdam 3015GE, the Netherlands. AD - Center for Lysosomal and Metabolic Diseases, Erasmus MC University Medical Center, Rotterdam 3015GE, the Netherlands. FAU - Stok, Merel AU - Stok M AD - Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam 3015GE, the Netherlands. AD - Department of Pediatrics, Erasmus MC University Medical Center, Rotterdam 3015GE, the Netherlands. AD - Center for Lysosomal and Metabolic Diseases, Erasmus MC University Medical Center, Rotterdam 3015GE, the Netherlands. AD - Department of Hematology, Erasmus MC University Medical Center, Rotterdam 3015GE, the Netherlands. FAU - van Helsdingen, Yvette AU - van Helsdingen Y AD - Department of Hematology, Erasmus MC University Medical Center, Rotterdam 3015GE, the Netherlands. FAU - Vulto, Arnold G AU - Vulto AG AD - Hospital Pharmacy, Erasmus MC University Medical Center, Rotterdam 3015GE, the Netherlands. FAU - van der Ploeg, Ans T AU - van der Ploeg AT AD - Department of Pediatrics, Erasmus MC University Medical Center, Rotterdam 3015GE, the Netherlands. AD - Center for Lysosomal and Metabolic Diseases, Erasmus MC University Medical Center, Rotterdam 3015GE, the Netherlands. FAU - van Til, Niek P AU - van Til NP AD - Department of Hematology, Erasmus MC University Medical Center, Rotterdam 3015GE, the Netherlands. FAU - Pijnappel, W W M Pim AU - Pijnappel WWMP AD - Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam 3015GE, the Netherlands. AD - Department of Pediatrics, Erasmus MC University Medical Center, Rotterdam 3015GE, the Netherlands. AD - Center for Lysosomal and Metabolic Diseases, Erasmus MC University Medical Center, Rotterdam 3015GE, the Netherlands. LA - eng PT - Journal Article DEP - 20220924 PL - United States TA - Mol Ther Methods Clin Dev JT - Molecular therapy. Methods & clinical development JID - 101624857 PMC - PMC9573825 OTO - NOTNLM OT - GAA OT - IGF2 OT - Pompe OT - gene therapy OT - glycogen storage disease OT - hematopoietic OT - lentiviral COIS- A.v.d.P. has received consulting fees from Sanofi Genzyme and has provided consulting services, participated in advisory board meetings, and received grants for premarketing studies and research from industries via agreements between Erasmus MC and the industry. N.v.T. is currently an employee of AVROBIO, Inc., Cambridge, MA, United States. M.S. is currently an employee of ProPharma Group, Leiden, the Netherlands. Contributions from N.v.T. and M.S. were made during their employment at Erasmus MC and were made independent of their current affiliations. EDAT- 2022/10/27 06:00 MHDA- 2022/10/27 06:01 PMCR- 2022/09/24 CRDT- 2022/10/26 02:08 PHST- 2021/12/02 00:00 [received] PHST- 2022/09/21 00:00 [accepted] PHST- 2022/10/26 02:08 [entrez] PHST- 2022/10/27 06:00 [pubmed] PHST- 2022/10/27 06:01 [medline] PHST- 2022/09/24 00:00 [pmc-release] AID - S2329-0501(22)00135-8 [pii] AID - 10.1016/j.omtm.2022.09.010 [doi] PST - epublish SO - Mol Ther Methods Clin Dev. 2022 Sep 24;27:109-130. doi: 10.1016/j.omtm.2022.09.010. eCollection 2022 Dec 8.