Pre-clinical Safety and Efficacy of Lentiviral Vector-Mediated Ex Vivo Stem Cell Gene Therapy for the Treatment of Mucopolysaccharidosis IIIACitation formats
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Pre-clinical Safety and Efficacy of Lentiviral Vector-Mediated Ex Vivo Stem Cell Gene Therapy for the Treatment of Mucopolysaccharidosis IIIA. / Ellison, Stuart M.; Liao, Aiyin; Wood, Shaun; Taylor, Jessica; Youshani, Amir Saam; Rowlston, Sam; Parker, Helen; Armant, Myriam; Biffi, Alessandra; Chan, Lucas; Farzaneh, Farzin; Wynn, Rob; Jones, Simon A.; Heal, Paul; Gaspar, H. Bobby; Bigger, Brian W.
In: Molecular Therapy - Methods and Clinical Development, Vol. 13, 14.06.2019, p. 399-413.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Pre-clinical Safety and Efficacy of Lentiviral Vector-Mediated Ex Vivo Stem Cell Gene Therapy for the Treatment of Mucopolysaccharidosis IIIA
AU - Ellison, Stuart M.
AU - Liao, Aiyin
AU - Wood, Shaun
AU - Taylor, Jessica
AU - Youshani, Amir Saam
AU - Rowlston, Sam
AU - Parker, Helen
AU - Armant, Myriam
AU - Biffi, Alessandra
AU - Chan, Lucas
AU - Farzaneh, Farzin
AU - Wynn, Rob
AU - Jones, Simon A.
AU - Heal, Paul
AU - Gaspar, H. Bobby
AU - Bigger, Brian W.
PY - 2019/6/14
Y1 - 2019/6/14
N2 - 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.
AB - 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.
U2 - 10.1016/j.omtm.2019.04.001
DO - 10.1016/j.omtm.2019.04.001
M3 - Article
AN - SCOPUS:85064563374
VL - 13
SP - 399
EP - 413
JO - Molecular Therapy - Methods & Clinical Development
JF - Molecular Therapy - Methods & Clinical Development
SN - 2329-0501
ER -