Prime and Base Editing Correct ALS-Causing SOD1 Mutations in Human Stem Cells

Scientists have corrected two disease-causing mutations in the SOD1 gene—one of the major genetic causes of familial amyotrophic lateral sclerosis—directly in human induced pluripotent stem cells, including cells derived from patients. The study, published in BMC Medical Genomics, reports optimized prime editing and base editing configurations that repaired the mutations with efficiencies of roughly 10% and 25%, respectively, in disease-relevant human cellular models.

Amyotrophic lateral sclerosis is a fatal neurodegenerative disorder characterized by progressive motor neuron degeneration and respiratory failure. About 10% of ALS cases are familial, and mutations in SOD1 represent a major genetic cause of these inherited forms. Because preserving the gene’s normal physiological function may be important, the researchers pursued mutation-specific gene correction as a complementary therapeutic strategy—one that would fix the defective sequence rather than silence or remove the gene entirely.

The team focused on two clinically relevant SOD1 mutations. The first, G93A, is a mutation widely used in animal models of ALS. The second, L126S, is a mutation enriched among Japanese patients. Induced pluripotent stem cells, including patient-derived lines, served as the disease-relevant human cellular platforms, allowing systematic screening and comparative evaluation of genome editing strategies within defined genetic backgrounds.

They conducted a screen of pegRNAs—the extended guide RNAs that direct prime editing—in human iPSCs carrying the mutation. This screening identified an optimized configuration that achieved approximately 10% precise correction efficiency. Notably, similar editing rates were observed when the same approach was evaluated in mouse iPSCs derived from ALS model mice, suggesting the configuration performs consistently across species.

For the L126S mutation, the team took a different approach, screening three cytosine base editors—BE4, YE1, and AID2S—in combination with guide RNAs in patient-derived iPSCs. The comparison showed that BE4 achieved the highest correction efficiency, reaching approximately 25% in the patient-derived cells and outperforming both YE1 and AID2S.

The work is significant because it demonstrates the feasibility of mutation-specific genome correction in human disease-relevant cellular models rather than in simplified or non-human systems alone. Patient-derived iPSCs carry the exact genetic background of the disease, making them a more faithful testing ground for editing strategies intended for eventual therapeutic use.

The authors emphasize that these findings highlight the potential of iPSC-based platforms for the preclinical development of mutation-corrective gene therapy for SOD1-associated familial ALS. In other words, the edited stem cells provide a way to compare editing strategies, optimize guide designs, and evaluate outcomes before any such approach could be considered for clinical translation.

Important limitations remain. The corrections were performed in stem cells in the laboratory, not in patients or even in animal models of disease progression, and the reported efficiencies—roughly 10% for prime editing of G93A and roughly 25% for base editing of L126S—reflect editing rates in cell culture. The study establishes optimized editing configurations and a screening framework; it does not report therapeutic efficacy in humans. ALS is a fatal neurodegenerative disorder, and any path from corrected stem cells toward a treatment for patients would require extensive additional preclinical work.

Even so, the study offers a concrete demonstration that two distinct precision genome editing modalities can be tuned, side by side, for different SOD1 mutations in the same human cellular platform. By pairing prime editing for one mutation with comparative base editor screening for another, and by validating the prime editing configuration in both human and mouse iPSCs, the researchers have laid out a systematic pipeline that other groups working on mutation-corrective gene therapy for familial ALS may be able to adapt.

Subject of Research: Mutation-specific prime and base editing correction of SOD1 mutations in patient-derived induced pluripotent stem cells for familial ALS

Article Title: Mutation-specific correction of SOD1 in familial ALS using prime and base editing in human induced pluripotent stem cells

Article References: Imamura, K., Tsukita, K., Yoshioka, S., Okusa, A., Mitsunobu, H., Woltjen, K., Nishida, K., Izumi, Y., & Inoue, H. (2026). Mutation-specific correction of SOD1 in familial ALS using prime and base editing in human induced pluripotent stem cells. BMC Medical Genomics. https://doi.org/10.1186/s12920-026-02492-6

Image Credits: AI Generated

DOI: 10.1186/s12920-026-02492-6

Keywords: ALS, SOD1, prime editing, base editing, induced pluripotent stem cells, gene correction, familial ALS, G93A, L126S, genome editing, BMC Medical Genomics, patient-derived cells