Department of Biosciences and Nutrition, Center for Innovative Medicine, Karolinska Institutet, Huddinge, Sweden.
Center for Genome Engineering, Institute for Basic Science (IBS), Dajeon, South Korea.
Nat Commun. 2022 Jun 2;13(1):3068. doi: 10.1038/s41467-022-30800-y.
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.
亨廷顿舞蹈病-早老综合征（Hutchinson-Gilford progeria syndrome，HGPS）是一种罕见的早发性衰老疾病，由 LMNA 基因（LMNA c.1824 C>T）的点突变引起，导致产生一种称为 progerin 的有害蛋白。腺嘌呤碱基编辑器最近在 HGPS 基因治疗方面展现出了巨大的潜力。然而，目前用于基因编辑的腺相关病毒载体系统存在一些问题，而且在皮肤等高度增殖组织中进行异质性突变校正的长期影响尚不清楚。在这里，我们使用一种非整合的瞬时慢病毒载体系统，表达腺嘌呤碱基编辑器，在 HGPS 小鼠的皮肤中纠正 HGPS 突变。瞬时腺嘌呤碱基编辑器的表达纠正了 20.8-24.1%的皮肤细胞中的突变。递送后 4 周，HGPS 皮肤表型得到改善，并检测到了 progerin 阴性角质形成细胞簇，表明突变在祖细胞和分化的皮肤细胞中都得到了纠正。这些结果表明，瞬时非整合病毒载体介导的腺嘌呤碱基编辑器表达是未来基因编辑治疗的一种可行方法。
