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Design and validation of a GMP stem cell manufacturing protocol for MPSII hematopoietic stem cell gene therapy

Authors :
Stuart Ellison
Karen Buckland
Yuko Learmonth
Victoria Day
Spandan Kalra
Lauren Howe
Francisco José Roman-Rodriguez
Jose Bonafont
Laura Booth
Rebecca Holley
Jon Smythe
Simon Jones
Adrian Thrasher
Claire Booth
Brian W. Bigger
Source :
Molecular Therapy: Methods & Clinical Development, Vol 32, Iss 2, Pp 101271- (2024)
Publication Year :
2024
Publisher :
Elsevier, 2024.

Abstract

Hematopoietic stem cell gene therapy (HSCGT) is a promising therapeutic strategy for the treatment of neurodegenerative, metabolic disorders. The approach involves the ex vivo introduction of a missing gene into patients’ own stem cells via lentiviral-mediated transduction (TD). Once transplanted back into a fully conditioned patient, these genetically modified HSCs can repopulate the blood system and produce the functional protein, previously absent or non-functional in the patient, which can then cross-correct other affected cells in somatic organs and the central nervous system. We previously developed an HSCGT approach for the treatment of Mucopolysaccharidosis type II (MPSII) (Hunter syndrome), a debilitating pediatric lysosomal disorder caused by mutations in the iduronate-2-sulphatase (IDS) gene, leading to the accumulation of heparan and dermatan sulfate, which causes severe neurodegeneration, skeletal abnormalities, and cardiorespiratory disease. In HSCGT proof-of-concept studies using lentiviral IDS fused to a brain-targeting peptide ApoEII (IDS.ApoEII), we were able to normalize brain pathology and behavior of MPSII mice. Here we present an optimized and validated good manufacturing practice hematopoietic stem cell TD protocol for MPSII in preparation for first-in-man studies. Inclusion of TEs LentiBOOST and protamine sulfate significantly improved TD efficiency by at least 3-fold without causing adverse toxicity, thereby reducing vector quantity required.

Details

Language :
English
ISSN :
23290501
Volume :
32
Issue :
2
Database :
Directory of Open Access Journals
Journal :
Molecular Therapy: Methods & Clinical Development
Publication Type :
Academic Journal
Accession number :
edsdoj.6d56cc1cb214a2393e79a6e7acc9046
Document Type :
article
Full Text :
https://doi.org/10.1016/j.omtm.2024.101271