Therapeutic Application of mRNA for Genetic Diseases

Abstract

While gene therapy has been at the center of an active research field for decades, messenger RNA (mRNA) has long been considered unsuited for therapeutic application due to challenges with stability, immunogenicity, and delivery. Where gene therapy focuses on providing the desired genetic code, mRNA can directly provide the instructions encoded in the corresponding gene. This review aims to explore recent advances in mRNA therapies, building on the success of mRNA COVID-19 vaccines, and extend these insights to the potential treatment of rare genetic diseases. We follow the “outside-in” trajectory of mRNA therapies from administration to intracellular function, focusing on carrier systems such as lipid nanoparticles and virus-like particles, mRNA modifications, and the potential and challenges for clinical applications. To treat rare diseases, different approaches can be envisioned, including chronic or acute delivery of mRNAs encoding functional enzymes for enzyme deficiencies and delivery of CRISPR/Cas9–based gene-editing tools for gene correction. These different approaches determine safety and immunological considerations. By exploring genetic, technical, and therapeutic aspects, this review highlights the potential and current challenges of mRNA therapies to address the large unmet needs in rare genetic disorders.