PMID- 38033460 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20231202 IS - 2329-0501 (Print) IS - 2329-0501 (Electronic) IS - 2329-0501 (Linking) VI - 31 DP - 2023 Dec 14 TI - Tagged IDS causes efficient and engraftment-independent prevention of brain pathology during lentiviral gene therapy for Mucopolysaccharidosis type II. PG - 101149 LID - 10.1016/j.omtm.2023.101149 [doi] LID - 101149 AB - Mucopolysaccharidosis type II (OMIM 309900) is a lysosomal storage disorder caused by iduronate 2-sulfatase (IDS) deficiency and accumulation of glycosaminoglycans, leading to progressive neurodegeneration. As intravenously infused enzyme replacement therapy cannot cross the blood-brain barrier (BBB), it fails to treat brain pathology, highlighting the unmet medical need to develop alternative therapies. Here, we test modified versions of hematopoietic stem and progenitor cell (HSPC)-mediated lentiviral gene therapy (LVGT) using IDS tagging in combination with the ubiquitous MND promoter to optimize efficacy in brain and to investigate its mechanism of action. We find that IDS tagging with IGF2 or ApoE2, but not RAP12x2, improves correction of brain heparan sulfate and neuroinflammation at clinically relevant vector copy numbers. HSPC-derived cells engrafted in brain show efficiencies highest in perivascular areas, lower in choroid plexus and meninges, and lowest in parenchyma. Importantly, the efficacy of correction was independent of the number of brain-engrafted cells. These results indicate that tagged versions of IDS can outperform untagged IDS in HSPC-LVGT for the correction of brain pathology in MPS II, and they imply both cell-mediated and tag-mediated correction mechanisms, including passage across the BBB and increased uptake, highlighting their potential for clinical translation. CI - (c) 2023 The Authors. 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 - Katsavelis, Drosos AU - Katsavelis D 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 - Dammou, Zina AU - Dammou Z 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 - Huizer, Tessa F AU - Huizer TF 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 - van den Bosch, Jeroen C AU - van den Bosch JC AD - Department of Clinical Genetics, 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 - Hoogeveen-Westerveld, Marianne AU - Hoogeveen-Westerveld M AD - Department of Clinical Genetics, 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 den Hout, Hannerieke J M P AU - van den Hout HJMP 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 - Oussoren, Esmeralda AU - Oussoren E 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 - Ruijter, George J G AU - Ruijter GJG AD - Department of Clinical Genetics, 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 - Schaaf, Gerben AU - Schaaf G 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 - Pike-Overzet, Karin AU - Pike-Overzet K AD - Department of Immunology, Leiden University Medical Center, Leiden 2333ZA, the Netherlands. FAU - Staal, Frank J T AU - Staal FJT AD - Department of Immunology, Leiden University Medical Center, Leiden 2333ZA, the Netherlands. AD - Department of Pediatrics, Leiden University Medical Center, Leiden 2333ZA, 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 - 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 - 20231102 PL - United States TA - Mol Ther Methods Clin Dev JT - Molecular therapy. Methods & clinical development JID - 101624857 PMC - PMC10684800 OTO - NOTNLM OT - ApoE2 OT - Hunter disease OT - IDS OT - IGF2 OT - RAP OT - lentiviral gene therapy OT - microglia OT - mucopolysaccharidosis type II OT - tagging OT - transcytosis COIS- A.T.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. W.W.M.P.P. and A.T.v.d,P. are advisors of LentiCure B.V., a company for the development of lentiviral gene therapy. F.C., E.C.V., A.T.v.d.P., and W.W.M.P.P. are inventors on patents in the field of lentiviral gene therapy. EDAT- 2023/11/30 18:45 MHDA- 2023/11/30 18:46 PMCR- 2023/11/02 CRDT- 2023/11/30 17:17 PHST- 2023/06/28 00:00 [received] PHST- 2023/10/31 00:00 [accepted] PHST- 2023/11/30 18:46 [medline] PHST- 2023/11/30 18:45 [pubmed] PHST- 2023/11/30 17:17 [entrez] PHST- 2023/11/02 00:00 [pmc-release] AID - S2329-0501(23)00188-2 [pii] AID - 101149 [pii] AID - 10.1016/j.omtm.2023.101149 [doi] PST - epublish SO - Mol Ther Methods Clin Dev. 2023 Nov 2;31:101149. doi: 10.1016/j.omtm.2023.101149. eCollection 2023 Dec 14.