Toward the full potential of mRNA therapeutics

The unprecedented rapid development and spectacular successes of the COVID-19 mRNA vaccines led many to expect rapid deployment of mRNA therapeutics for a wide range of unmet needs that this technology platform appears well-suited to address. 1 Baden L.R. El Sahly H.M. Essink B. Kotloff K. Frey S. Novak R. Diemert D. Spector S.A. Rouphael N. Creech C.B. et al. Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. N. Engl. J. Med. 2021; 384: 403-416https://doi.org/10.1056/NEJMoa2035389 Google Scholar ,2 Polack F.P. Thomas S.J. Kitchin N. Absalon J. Gurtman A. Lockhart S. Perez J.L. Pérez Marc G. Moreira E.D. Zerbini C. et al. Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. N. Engl. J. Med. 2020; 383: 2603-2615https://doi.org/10.1056/NEJMoa2034577 Google Scholar Indeed, exciting progress has been made in the mRNA therapeutics field since the vaccines were approved. 3 Youssef M. Hitti C. Puppin Chaves Fulber J. Kamen A.A. Enabling mRNA Therapeutics: Current Landscape and Challenges in Manufacturing. Biomolecules. 2023; 131497https://doi.org/10.3390/biom13101497 Google Scholar However, until a report by Koeberl et al. in Nature last month, mRNA therapies with the attributes needed for broad applicability to chronic diseases (i.e., efficacy and safety upon repeat dosing via systemic administration) had yet to be demonstrated in clinical trials. 4 Koeberl D. Schulze A. Sondheimer N. Lipshutz G.S. Geberhiwot T. Li L. Saini R. Luo J. Sikirica V. Jin L. et al. Interim analyses of a first-in-human phase 1/2 mRNA trial for propionic acidaemia. Nature. 2024; 628: 872-877https://doi.org/10.1038/s41586-024-07266-7 Google Scholar This small study reports interim analyses of a clinical trial for mRNA-3927, an mRNA therapy developed by Moderna for propionic acidemia (PA), a rare heritable metabolic disease. 4 Koeberl D. Schulze A. Sondheimer N. Lipshutz G.S. Geberhiwot T. Li L. Saini R. Luo J. Sikirica V. Jin L. et al. Interim analyses of a first-in-human phase 1/2 mRNA trial for propionic acidaemia. Nature. 2024; 628: 872-877https://doi.org/10.1038/s41586-024-07266-7 Google Scholar The results are preliminary, and the trial has important limitations including the small number of participants and the lack of a control group. That said, the results regarding safety and efficacy so far are promising (see below). The study is a milestone for mRNA therapeutics, as it is the first description of chronic dosing of a lipid-nanoparticle-encapsulated mRNA therapy administered systemically in humans.