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Human artificial chromosomes for Duchenne muscular dystrophy and beyond: challenges and hopes

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Abstract

Safe and efficacious vectors able to carry large or several transgenes are of key importance for gene therapy. Human artificial chromosomes can fulfil this essential requirement; moreover, they do not integrate into the host genome. However, drawbacks such as the low efficiency of chromosome transfer and their relatively complex engineering still limit their widespread use. In this article, I summarise the key steps that brought human artificial chromosomes into preclinical research for Duchenne muscular dystrophy, an X-linked, monogenic disorder. I will also review possible future pre-clinical and clinical perspectives for this technology.

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Abbreviations

AAV:

Adeno-associated viral (vectors)

cDNA:

Complementary DNA

CHO:

Chinese hamster ovary (cells)

DMD:

Duchenne muscular dystrophy

DT40:

Chicken B cell line (lymphoblasts)

DYS-HAC:

Dystrophin-HAC

GFP:

Green fluorescent protein

HAC:

Human artificial chromosome

iPS:

Induced pluripotent stem (cells)

MMCT:

Microcell-mediated chromosome transfer

PEG:

Polyethylene glycol

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Acknowledgments

The author thanks Mitsuo Oshimura, Narumi Uno, Yasuhiro Kazuki, Giulio Cossu, Hidetoshi Hoshiya and all laboratory members for the active discussions on HAC technology and the helpful suggestions on the manuscript. Work in the author’s laboratory is supported by the UK Medical Research Council (MRC grants no. MR/J006785/1 and MR/L002752/1), Duchenne Parent Project Onlus, European Union’s 7th Framework Programme (PluriMes project, grant no. 602423), Takeda New Frontier Science, Biotechnology and Biological Sciences Research Council (BBSRC), Muscular Dystrophy Campaign, Duchenne Children’s Trust and the Duchenne Research Fund.

Conflict of interest

The author declares no conflict of interest.

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  1. Department of Cell and Developmental Biology, University College London, 21 University Street, London, WC1E 6DE, UK

    Francesco Saverio Tedesco

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  1. Francesco Saverio Tedesco
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Correspondence to Francesco Saverio Tedesco.

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Responsible Editors: Natalay Kouprina and Vladimir Larionov

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Tedesco, F.S. Human artificial chromosomes for Duchenne muscular dystrophy and beyond: challenges and hopes. Chromosome Res 23, 135–141 (2015). https://doi.org/10.1007/s10577-014-9460-6

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