||Near-Complete Genetic Engineering of Hematopoiesis with Substantial Therapeutic Benefit in Metachromatic Leukodystrophy after Lentiviral Hematopoietic Stem Cell Gene Therapy
|演者||Luigi Naldini, M.D. , PhD.
Professor, San Raffaele Telethon Institute for Gene Therapy and
Vita Salute San Raffaele University, Milan, Italy
|場所||馬出医学系キャンパス内 総合研究棟 セミナー室 １０５
Metachromatic Leukodystrophy (MLD) is an autosomal recessive lysosomal storage disorder, characterized by inherited deficiency of the enzyme Arylsulfatase A (ARSA) and leading to severe progressive demyelination and neurodegeneration. Currently, no treatment can halt the progression or substantially delay the fatal outcome of this devastating disease. Whereas Hematopoietic Stem Cell (HSC) transplantation fails to provide consistent benefits in MLD, our preclinical studies had demonstrated that HSC gene therapy could prevent and correct the disease manifestations in the mouse model, based on the possibility to achieve extensive and supra-normal enzyme expression throughout the HSC progeny, which mediate widespread cross-correction of resident cells in the central and peripheral nervous system. Based on these studies and the development of a HSC transduction protocol attaining substantial levels of gene transfer, we have started a clinical trial of HSC gene therapy in early onset MLD. We report stable sustained ARSA gene replacement to nearly exhaustive levels in the reconstituted hematopoiesis of the first three treated late infantile MLD patients, resulting in supra-normal ARSA expression throughout the hematopoietic lineages. By ultra-deep monitoring of lentiviral vector integration sites we showed that the high gene marking levels were the results of highly polyclonal engraftment by the transduced cells, without evidence of aberrant clonal behavior ascribed to specific vector insertion. Importantly, the unprecedented extent of gene replacement achieved in post-transplant hematopoiesis was associated with substantial therapeutic benefit, as the disease had not progressed in any of the treated patients at the latest follow-up.