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

Research output: Contribution to journalArticlepeer-review

  • External authors:
  • Aiyin Liao
  • Jessica Taylor
  • Amir Saam Youshani
  • Sam Rowlston
  • Myriam Armant
  • Alessandra Biffi
  • Lucas Chan
  • Farzin Farzaneh
  • Rob Wynn
  • Simon A. Jones
  • Paul Heal
  • H. Bobby Gaspar


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.

Bibliographical metadata

Original languageEnglish
Pages (from-to)399-413
Number of pages15
JournalMolecular Therapy - Methods and Clinical Development
Early online date6 Apr 2019
Publication statusPublished - 14 Jun 2019