Transient expression of an adenine base editor corrects the Hutchinson-Gilford progeria syndrome mutation and improves the skin phenotype in mice

Daniel Whisenant, Kayeong Lim, Gwladys Revêchon, Haidong Yao, Martin O. Bergo, Piotr Machtel, Jin-Soo Kim and Maria Eriksson ()
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Daniel Whisenant: Karolinska Institutet
Kayeong Lim: Institute for Basic Science (IBS)
Gwladys Revêchon: Karolinska Institutet
Haidong Yao: Karolinska Institutet
Martin O. Bergo: Karolinska Institutet
Piotr Machtel: Karolinska Institutet
Jin-Soo Kim: Institute for Basic Science (IBS)
Maria Eriksson: Karolinska Institutet

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: Abstract Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature ageing disorder caused by a point mutation in the LMNA gene (LMNA c.1824 C > T), resulting in the production of a detrimental protein called progerin. Adenine base editors recently emerged with a promising potential for HGPS gene therapy. However adeno-associated viral vector systems currently used in gene editing raise concerns, and the long-term effects of heterogeneous mutation correction in highly proliferative tissues like the skin are unknown. Here we use a non-integrative transient lentiviral vector system, expressing an adenine base editor to correct the HGPS mutation in the skin of HGPS mice. Transient adenine base editor expression corrected the mutation in 20.8-24.1% of the skin cells. Four weeks post delivery, the HGPS skin phenotype was improved and clusters of progerin-negative keratinocytes were detected, indicating that the mutation was corrected in both progenitor and differentiated skin cells. These results demonstrate that transient non-integrative viral vector mediated adenine base editor expression is a plausible approach for future gene-editing therapies.

Date: 2022
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DOI: 10.1038/s41467-022-30800-y

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