Fig. 1

Illustration of ALS gene therapy strategies using SOD1 mutations as an example. (1) ASOs are short, synthetic RNA or DNA strands, typically designed to be complementary to specific mRNA sequences within cells. Upon binding to their target mRNA, ASOs recruit RNase H, which recognizes the RNA–DNA or RNA-RNA duplex formed by the ASO and its target mRNA. RNase H then cleaves the mRNA strand of the duplex, reducing the production of the protein encoded by the mRNA. (2) siRNAs are completely complementary to their target mRNAs, leading RISC to directly cleave the target mRNAs, resulting in their degradation. miRNAs, on the other hand, are partially complementary to their target mRNAs, typically binding to the 3′ untranslated region (3′ UTR), where they primarily inhibit translation or cause mRNA destabilization and degradation. (3) CRISPR gene editing employs a gRNA to direct the Cas9 enzyme to specific locations in the DNA. After binding to the target DNA sequence, Cas9 induces double-strand breaks in the DNA. The cell then initiates repair processes, which can be harnessed to introduce changes to the gene sequence, such as knocking out harmful genes or correcting mutations. (4) Various gene delivery vehicles, including AAV, nanoparticles, liposomes, and protein carriers, are used to enhance the precise delivery of ASOs, RNAi agents, CRISPR-Cas9 agents, neurotrophic factors, and other therapeutic agents, thereby improving their transport efficiency. Figure Created with BioRender.com