Tagged IDS causes efficient and engraftment-independent prevention of brain pathology during lentiviral gene therapy for Mucopolysaccharidosis type II

Fabio Catalano; Eva C Vlaar; Drosos Katsavelis; Zina Dammou; Tessa F Huizer; Jeroen C van den Bosch; Marianne Hoogeveen-Westerveld; Hannerieke J M P van den Hout; Esmeralda Oussoren; George J G Ruijter; Gerben Schaaf; Karin Pike-Overzet; Frank J T Staal; Ans T van der Ploeg; W W M Pim Pijnappel

doi:10.1016/j.omtm.2023.101149

Tagged IDS causes efficient and engraftment-independent prevention of brain pathology during lentiviral gene therapy for Mucopolysaccharidosis type II

Mol Ther Methods Clin Dev. 2023 Nov 2:31:101149. doi: 10.1016/j.omtm.2023.101149. eCollection 2023 Dec 14.

Authors

Fabio Catalano^{1

2

3}, Eva C Vlaar^{1

2

3}, Drosos Katsavelis^{1

2

3}, Zina Dammou^{1

2

3}, Tessa F Huizer^{1

2

3}, Jeroen C van den Bosch^{1

3}, Marianne Hoogeveen-Westerveld^{1

3}, Hannerieke J M P van den Hout^{2

3}, Esmeralda Oussoren^{2

3}, George J G Ruijter^{1

3}, Gerben Schaaf^{1

2

3}, Karin Pike-Overzet⁴, Frank J T Staal^{4

5}, Ans T van der Ploeg^{2

3}, W W M Pim Pijnappel^{1

2

3}

Affiliations

¹ Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam 3015GE, the Netherlands.
² Department of Pediatrics, Erasmus MC University Medical Center, Rotterdam 3015GE, the Netherlands.
³ Center for Lysosomal and Metabolic Diseases, Erasmus MC University Medical Center, Rotterdam 3015GE, the Netherlands.
⁴ Department of Immunology, Leiden University Medical Center, Leiden 2333ZA, the Netherlands.
⁵ Department of Pediatrics, Leiden University Medical Center, Leiden 2333ZA, the Netherlands.

Abstract

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.

Keywords: ApoE2; Hunter disease; IDS; IGF2; RAP; lentiviral gene therapy; microglia; mucopolysaccharidosis type II; tagging; transcytosis.