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

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

Standard

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 journalArticle

Harvard

Ellison, SM, Liao, A, Wood, S, Taylor, J, Youshani, AS, Rowlston, S, Parker, H, Armant, M, Biffi, A, Chan, L, Farzaneh, F, Wynn, R, Jones, SA, Heal, P, Gaspar, HB & Bigger, BW 2019, 'Pre-clinical Safety and Efficacy of Lentiviral Vector-Mediated Ex Vivo Stem Cell Gene Therapy for the Treatment of Mucopolysaccharidosis IIIA' Molecular Therapy - Methods and Clinical Development, vol. 13, pp. 399-413. https://doi.org/10.1016/j.omtm.2019.04.001

APA

Vancouver

Author

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. / Pre-clinical Safety and Efficacy of Lentiviral Vector-Mediated Ex Vivo Stem Cell Gene Therapy for the Treatment of Mucopolysaccharidosis IIIA. In: Molecular Therapy - Methods and Clinical Development. 2019 ; Vol. 13. pp. 399-413.

Bibtex

@article{b5f82d19687641fd941d0766150d20c2,
title = "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.",
author = "Ellison, {Stuart M.} and Aiyin Liao and Shaun Wood and Jessica Taylor and Youshani, {Amir Saam} and Sam Rowlston and Helen Parker and Myriam Armant and Alessandra Biffi and Lucas Chan and Farzin Farzaneh and Rob Wynn and Jones, {Simon A.} and Paul Heal and Gaspar, {H. Bobby} and Bigger, {Brian W.}",
year = "2019",
month = "6",
day = "14",
doi = "10.1016/j.omtm.2019.04.001",
language = "English",
volume = "13",
pages = "399--413",
journal = "Molecular Therapy - Methods & Clinical Development",
issn = "2329-0501",
publisher = "Springer Nature",

}

RIS

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

VL - 13

SP - 399

EP - 413

JO - Molecular Therapy - Methods & Clinical Development

JF - Molecular Therapy - Methods & Clinical Development

SN - 2329-0501

ER -