Said, H. | bioRxiv Science

bioRxiv2026

Correction of a recurrent pathogenic variant in methylmalonic acidemia using adenine base editing

Methylmalonic acidemia (MMA) is a recessive genetic disease caused by variants in the MMUT (mitochondrial enzyme methylmalonyl-CoA mutase) gene or by defects in transport or metabolism of MMUT cofactor (5 deoxyadenosylcobalamin), including variants in the MMAB gene. For the most recurrent pathogenic MMAB variant, c.556C>T (R186W), we identified a corrective editing strategy using adenine base editing. Deploying an adenine base editor mRNA and optimized hybrid guide RNA with lipid nanoparticles, we observed efficient in vitro corrective editing of the variant to wild-type, with minimized bystander editing and off-target editing in hepatocytes. These observations lay the groundwork for a gene editing therapy for patients with MMA resulting from at least one copy of the MMAB c.556C>T (R186W) variant, as well as a platform of similar therapies for patients with MMA caused by other variants amenable to adenine base editing.

genetics↗

bioRxiv2025

The type I IFN-IL-27 axis promotes mRNA vaccine-induced CD8+ T cell responses

The ability of lipid nanoparticle (LNP)-delivered mRNA vaccines to induce type I IFNs is critical to promote CD8+ T cell responses. The studies presented here indicate that immunization with nucleoside modified mRNA-LNP vaccines drives myeloid cell expression of the cytokine IL-27, which acts on antigen-specific CD8+ T cells to sustain T cell expansion. In vitro and in vivo studies revealed that type I IFN signaling is necessary for mRNA-LNP-induced IL-27 production, that immunization failed in IL-27 KO mice, and that immunization of IFNAR1-deficient mice with mRNA-LNP particles that also encode IL-27 mRNA restored antigen-specific CD8+ T cell responses. In addition, IL-27 mRNA-LNPs served as an adjuvant that improved cytolytic CD8+ T cell responses and the therapeutic efficacy of mRNA-LNPs to drive anti-pathogen and anti-tumor immunity. These studies highlight the central role of IL-27 in mRNA-LNP induced CD8+ T cell responses and the ability of this cytokine to augment the functionality of the CD8+ T cell response for prophylactic or therapeutic immunization.

immunology↗