An empowered, clinically-viable hematopoietic stem cell gene therapy approach for the treatment of multisystemic Mucopolysaccharidosis Type II

: Mucopolysaccharidosis type II (MPS II), or Hunter syndrome, is a rare X-linked recessive lysosomal storage disorder due to a mutation in the lysosomal enzyme iduronate-2-sulfatase (IDS) gene. IDS-deficiency leads to a progressive, multisystem accumulation of glycosaminoglycans (GAGs) and results in central nervous system (CNS) manifestations in the severe form. We developed up to clinical readiness a new Hematopoietic Stem Cell (HSC) gene therapy approach for MPS II that benefits from a novel highly effective transduction protocol. We first provided proof-of-concept of efficacy of our approach aimed at enhanced IDS enzyme delivery to the CNS in a murine study of immediate translational value, employing a lentiviral vector (LV) encoding a codon optimized human IDS cDNA. Then the therapeutic LV was tested for its ability to efficiently and safely transduce bona fide human HSCs in clinically relevant conditions according to a standard versus a novel protocol that demonstrated superior ability to transduce bona fide long-term repopulating HSCs. Overall, these results provide strong proof-of-concept for the clinical translation of this approach for the treatment of Hunter syndrome.