Hematopoietic Stem Cell Gene Therapy Corrects Neuropathic Phenotype in Murine Model of Mucopolysaccharidosis Type II

Abstract

Mucopolysaccharidosis type II (MPS II) is a neuropathic lysosomal storage disorder caused by a deficiency of iduronate-2-sulfatase (IDS), which leads to the accumulation of glycosaminoglycans (GAGs). We demonstrated that biochemical alterations in the brains of MPS II mice are not corrected by bone marrow transplantation (BMT) or enzyme replacement therapy, although BMT has been shown to be effective for other neurodegenerative MPSs, such as Hurler syndrome. In this study, we demonstrated that lentiviral isogeneic hematopoietic stem cell (HSC) gene therapy corrected neuronal manifestations by ameliorating lysosomal storage and autophagic dysfunction in the brains of MPS II mice. IDS-transduced HSCs increased enzyme activity both in various visceral organs and the CNS. Decreased levels of GAGs were observed in many organs, including cerebra, after transplantation of IDS-transduced HSCs. In addition, lentiviral HSC gene therapy normalized the secondary accumulation of autophagic substrates, such as p62 and ubiquitin-protein conjugates, in cerebra. Furthermore, in contrast to naive MPS II mice, there was no deterioration of neuronal function observed in transplant recipients. These results indicated that lentiviral HSC gene therapy is a promising approach for the treatment of CNS lesions in MPS II.

Harnessing host–virus evolution in antiviral therapy and immunotherapy

“…Since viruses typically infect and replicate best in only a limited set of host tissues, delivering therapies to specific tissues may mitigate adverse effects. Synthetic lipid nanoparticles (LNPs) protect and deliver small RNAs for RNAi‐based therapy as well as synthetic vaccines and bioactive compounds, while modified viruses or virus‐like particles deliver RNA interference (RNAi)‐based therapies as well as nucleases and DNA for gene therapy . Despite additional challenges as outlined below, these technologies are currently applied to deliver specific treatments for viral infection, cardiovascular disease, inherited genetic disorders and cancer immunotherapy in animal models and humans …”

Innovative Treatments for Mucopolysaccharidoses

“…In this sense, mouse models of Hunters and Sanfilippo A disease have been successfully treated with autologous HSC transduced with a lentivirus encoding for iduronate-2-sulfatase and N-sulfoglucosamine sulfohydrolase, respectively. 54,55 Interestingly, in contrast to regular HSCT these modified HSC improved neuropathology significantly. In metachromatic leukodystrophy, another LSD, this strategy has been successfully used in clinical trials.…”

“…Continued) Ex-vivo gene therapy with lentiviral corrected HSC in MPS II-mice54 Retroviral in-vivo gene therapy96 SB-913 AAV6/zinc finger nuclease mediated genome editing NCT03041324…”

Gene Therapy for Lysosomal Storage Disorders

“…36 A recent study demonstrated that although biochemical alterations in the brains of MPS II mice are not fully corrected by regular HSCT, curiously the HSCT modified with a lentivirus to overexpress iduronate sulfatase corrected neuronal manifestations in the brains of MPS II mice. 35 After preclinical studies, the use of these viruses finally reached the clinical stage. A lentiviral vector was used to transfer a functional Arylsulfatase A (ARSA) gene into HSCs from 3 presymptomatic patients with late infantile metachromatic leukodystrophy.…”