近日，中山大学黄军就及其研究团队发现，体内腺嘌呤碱基编辑可改善与Rho相关的常染色体显性视网膜色素变性。这一研究成果于2024年12月24日在线发表在《遗传学报》上。

研究人员表示，Rhodopsin（RHO）基因突变是常染色体显性视网膜色素变性（adRP）的主要原因，其中84%的突变是致病性功能获得型点突变。adRP的治疗策略通常涉及沉默或消除致病等位基因，而正常的RHO蛋白替代并没有显著的治疗效果。

研究人员提出了一种腺嘌呤碱基编辑器（ABE）介导的治疗方法，用于治疗由RHO点突变引起的adRP。研究人员筛选并验证了可纠正的致病突变，包括T17M、Q344ter和P347L。研究人员创建了两个adRP动物模型，分别携带1类（Q344ter）和2类（T17M）突变，并且双重AAV递送的ABE能够有效地在体内修复这两种突变。ABE8e的早期干预有效修复了Q344ter突变，这种突变会导致严重的adRP形式，延缓了光感受器死亡，并恢复了视网膜功能和视觉行为。

这些结果表明，ABE是治疗与RHO突变相关的adRP的有前景的替代方法。该研究提供了一种有效的间隔介导点突变修正疗法，用于显性遗传性眼部疾病的治疗。

附：英文原文

Title: In vivo adenine base editing ameliorates Rho-associated autosomal dominant retinitis pigmentosa

Author: Junjiu Huang a b

Issue&Volume: 2024/12/24

Abstract: Mutations in the Rhodopsin (RHO) gene are the main cause of autosomal dominant retinitis pigmentosa (adRP), 84% of which are pathogenic gain-of-function point mutations. Treatment strategies for adRP typically involve silencing or ablating the pathogenic allele, while normal RHO protein replacement has no meaningful therapeutic benefit. Here, we present an adenine base editor (ABE)-mediated therapeutic approach for adRP caused by RHO point mutations in vivo. The correctable pathogenic mutations are screened and verified, including T17M, Q344ter, and P347L. Two adRP animal models are created carrying the class 1 (Q344ter) and class 2 (T17M) mutations, and dual AAV-delivered ABE can effectively repair both mutations in vivo. The early intervention of ABE8e efficiently corrects the Q344ter mutation that causes a severe form of adRP, delays photoreceptor death, and restores retinal function and visual behavior. These results suggest that ABE is a promising alternative to treat RHO mutation-associated adRP. Our work provides an effective spacer-mediated point mutation correction therapy approach for dominantly inherited ocular disorders.

DOI: 10.1016/j.jgg.2024.12.012

Source: https://www.sciencedirect.com/science/article/abs/pii/S1673852724003655