TY - JOUR
T1 - Tagged IDS causes efficient and engraftment-independent prevention of brain pathology during lentiviral gene therapy for Mucopolysaccharidosis type II
AU - Catalano, Fabio
AU - Vlaar, Eva C.
AU - Katsavelis, Drosos
AU - Dammou, Zina
AU - Huizer, Tessa F.
AU - van den Bosch, Jeroen C.
AU - Hoogeveen-Westerveld, Marianne
AU - van den Hout, Hannerieke J.M.P.
AU - Oussoren, Esmeralda
AU - Ruijter, George J.G.
AU - Schaaf, Gerben
AU - Pike-Overzet, Karin
AU - Staal, Frank J.T.
AU - van der Ploeg, Ans T.
AU - Pijnappel, W. W.M.Pim
N1 - Publisher Copyright: © 2023 The Authors
PY - 2023/12/14
Y1 - 2023/12/14
N2 - 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.
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.
UR - http://www.scopus.com/inward/record.url?scp=85177031228&partnerID=8YFLogxK
U2 - 10.1016/j.omtm.2023.101149
DO - 10.1016/j.omtm.2023.101149
M3 - Article
C2 - 38033460
AN - SCOPUS:85177031228
SN - 2329-0501
VL - 31
JO - Molecular Therapy Methods and Clinical Development
JF - Molecular Therapy Methods and Clinical Development
M1 - 101149
ER -