Pre-clinical Safety and Efficacy of Lentiviral Vector-Mediated Ex Vivo Stem Cell Gene Therapy for the Treatment of Mucopolysaccharidosis IIIA

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.

Mucopolysaccharidosis IVA: Diagnosis, Treatment, and Management

“…Apart from the AAV-mediated treatment model, Orchard Therapeutics (London, UK) has started a Phase I/II ex vivo gene therapy using autologous CD34 + cells transfected with hSGSH-containing lentiviruses [134]. Pre-clinical data for this treatment modality demonstrated competency in meeting expected safety profiles and an effective transfection goal (2-5 copies/cell) [135]. This treatment model is the first of its kind in MPS clinical trials, and the preliminary results are highly anticipated.…”

Lentiviral Hematopoietic Stem Cell Gene Therapy Rescues Clinical Phenotypes in a Murine Model of Pompe Disease

“… 27 , 28 , 29 , 30 , 31 Similarly, promising results have been shown in pre-clinical studies in other lysosomal storage disorders such as globoid cell leukodystrophy 32 or mucopolysaccharidosis (MPS) diseases (MPS-I, MPS-II, or MPS-IIIA/B). 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 In these cases, the overexpression of the therapeutic gene in the HSPCs reduced the toxic accumulation of metabolites in affected tissues, ameliorating or even reverting, in the case of MPS-I, disease manifestations. Two previous studies looked at the feasibility of HSPC gene therapy in Pompe disease and showed a relevant decrease of glycogen accumulation in affected tissues upon treatment as well as the induction of immune tolerance versus hGAA in treated mice.…”

Sanfilippo Syndrome: Molecular Basis, Disease Models and Therapeutic Approaches

“…Nevertheless, this process seems to be slow and not complete, making this option an invalid therapy for neurological disorders with a rapid progress of symptoms such as Sanfilippo syndrome, and currently, this approach is no longer considered for the treatment of Sanfilippo syndrome [ 97 ]. However, recent works using genetically modified hematopoietic stem cells carrying the normal copy of the SGSH or NAGLU genes showed an improvement in the neurological pathology in MPS IIIA or MPS IIIB mouse models [ 98 , 99 , 100 , 101 ].…”