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The transformative potential of HSC gene therapy as a genetic medicine

Abstract

Hematopoietic stem cells (HSCs) are precursor cells that give rise to blood, immune and tissue-resident progeny in humans. Their position at the starting point of hematopoiesis offers a unique therapeutic opportunity to treat certain hematologic diseases by implementing corrective changes that are subsequently directed through to multiple cell lineages. Attempts to exploit HSCs clinically have evolved over recent decades, from initial approaches that focused on transplantation of healthy donor allogeneic HSCs to treat rare inherited monogenic hematologic disorders, to more contemporary genetic modification of autologous HSCs offering the promise of benefits to a wider range of diseases. We are on the cusp of an exciting new era as the transformative potential of HSC gene therapy to offer durable delivery of gene-corrected cells to a range of tissues and organs, including the central nervous system, is beginning to be realized. This article reviews the rationale for targeting HSCs, the approaches that have been used to date for delivering therapeutic genes to these cells, and the latest technological breakthroughs in manufacturing and vector design. The challenges faced by the biotechnology cell and gene therapy sector in the commercialization of HSC gene therapy are also discussed.

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Fig. 1: A combination of hematopoietic stem-cell self-renewal and lentiviral vector-mediated integration of the therapeutic gene into the hematopoietic stem-cell genome offers the potential for permanent correction.
Fig. 2: Gene therapy manufacturing and administration.
Fig. 3: Lentiviral vector design and gene transfer.
Fig. 4: Innovative approaches for transforming commercial gene therapy.

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Acknowledgements

We would like to thank Robin LeWinter, PhD, Leslie Meltzer, PhD and Denise Sarracino, PhD from Orchard Therapeutics (Europe) Ltd for their help coordinating the writing of the paper. Editorial support, based on authors’ direction, was provided by Ben Drever PhD from Comradis, UK, and was paid for by Orchard Therapeutics Ltd.

Funding

This research was supported by Orchard Therapeutics Ltd and medical writing assistance was provided by Ben Drever, PhD, of Comradis, UK and funded by Orchard Therapeutics Ltd.

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Correspondence to H. Bobby Gaspar.

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PS and HBG are employees of Orchard Therapeutics Ltd.

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Sagoo, P., Gaspar, H.B. The transformative potential of HSC gene therapy as a genetic medicine. Gene Ther (2021). https://doi.org/10.1038/s41434-021-00261-x

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