Abstract
Hematopoietic stem cell gene therapy is a promising therapeutic strategy for the treatment of neurological disorders, since transplanted gene-corrected cells can traffic to the brain, bypassing the blood-brain barrier, to deliver therapeutic protein to the CNS. We have developed this approach for the treatment of Mucopolysaccharidosis type IIIA (MPSIIIA), a devastating lysosomal storage disease that causes progressive cognitive decline, leading to death in early adulthood. In a previous pre-clinical proof-of-concept study, we demonstrated neurological correction of MPSIIIA utilizing hematopoietic stem cell gene therapy via a lentiviral vector encoding the SGSH gene. Prior to moving to clinical trial, we have undertaken further studies to evaluate the efficiency of gene transfer into human cells and also safety studies of biodistribution and genotoxicity. Here, we have optimized hCD34+ cell transduction with clinical grade SGSH vector to provide improved pharmacodynamics and cell viability and validated effective scale-up and cryopreservation to generate an investigational medicinal product. Utilizing a humanized NSG mouse model, we demonstrate effective engraftment and biodistribution, with no vector shedding or transmission to germline cells. SGSH vector genotoxicity assessment demonstrated low transformation potential, comparable to other lentiviral vectors in the clinic. This data establishes pre-clinical safety and efficacy of HSCGT for MPSIIIA.
Highlights
Mucopolysaccharidosis type IIIA (MPSIIIA), known as Sanfilippo syndrome A, is a severe, progressive, neurodegenerative disorder caused by loss-of-function mutations in the N-sulfoglucosamine sulfohydrolase (SGSH) gene.[1]
GMP CD11b.SGSH lentiviral vector (LV) Is Equivalent to Research Grade LV: In Vivo Vector-Bridging Study To develop hematopoietic stem cell gene therapy (HSCGT) for MPSIIIA patients, we produced a thirdgeneration self-inactivating (SIN) LV with a codon optimized SGSH transgene driven by the myeloid-specific CD11b promoter (CD11b.SGSH LV), manufactured to good manufacturing practice (GMP) standard (Figure 1A).[21]
There was no difference in transduction efficiency between vector grades in terms of vector copy numbers (VCNs); variation in integrated VCNs was observed between different transplant batches, likely due to differences between donor hematopoietic stem-cell-enriched cell lots (Figure 1D)
Summary
Mucopolysaccharidosis type IIIA (MPSIIIA), known as Sanfilippo syndrome A, is a severe, progressive, neurodegenerative disorder caused by loss-of-function mutations in the N-sulfoglucosamine sulfohydrolase (SGSH) gene.[1]. Disease pathology progressively worsens over time, and affected individuals do not typically survive beyond late teenage years or early adulthood
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