PDF(Pubmed)
Abstract：
Defect in the SMN1 gene causes spinal muscular atrophy (SMA), which shows loss of motor neurons, muscle weakness and atrophy. While current treatment strategies, including small molecules or viral vectors, have shown promise in improving motor function and survival, achieving a definitive and long-term correction of SMA\'s endogenous mutations and phenotypes remains highly challenging. We have previously developed a CRISPR-Cas9 based homology-independent targeted integration (HITI) strategy, enabling unidirectional DNA knock-in in both dividing and non-dividing cells in vivo. In this study, we demonstrated its utility by correcting an SMA mutation in mice. When combined with Smn1 cDNA supplementation, it exhibited long-term therapeutic benefits in SMA mice. Our observations may provide new avenues for the long-term and efficient treatment of inherited diseases.
摘要：
SMN1基因缺陷导致脊髓性肌萎缩(SMA),显示运动神经元的丢失，肌肉无力和萎缩。虽然目前的治疗策略，包括小分子或病毒载体，在改善运动功能和生存方面表现出了希望，实现SMA的内源性突变和表型的确定和长期校正仍然极具挑战性。我们之前已经开发了一种基于CRISPR-Cas9的非同源性靶向整合（HITI）策略，在体内分裂和非分裂细胞中实现单向DNA敲入。在这项研究中,我们通过纠正小鼠的SMA突变证明了其实用性。当与Smn1cDNA补充结合时，它在SMA小鼠中表现出长期治疗益处。我们的观察可能为遗传性疾病的长期有效治疗提供新的途径。
