Therapeutic strategy for spinal muscular atrophy by combining gene supplementation and genome editing

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 homologous recombination targeted integration (HITI) strategy, enabling successful knock-in both in 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 yielded long-term therapeutic benefits in SMA mice. Our observations provide new avenues for the long-term and efficient treatment of inherited diseases.

Fumiyuki Hatanaka, Keiichiro Suzuki, Kensaku Shojima, Jingting Yu, Yuta Takahashi, Akihisa Sakamoto, Javier Prieto, Maxim Shokhirev, Estrella Nuñez Delicado, Concepcion Rodriguez Esteban, Juan Carlos Izpisua Belmonte