A New Era for Rare Genetic Diseases: Messenger RNA Therapy.

Exogenous delivery of messenger RNA (mRNA) is emerging as a new class of medicine with broad applicability including the potential to treat rare monogenic disorders. Recent advances in mRNA technology, including modifications to the mRNA itself along with improvements to the delivery vehicle, have transformed the utility of mRNA as a potential therapy to restore or replace different types of therapeutic proteins. Preclinical proof-of-concept has been demonstrated for mRNA therapy for three different rare metabolic disorders: methylmalonic acidemia, acute intermittent porphyria, and Fabry disease. Herein, we review those preclinical efficacy and safety studies in multiple animal models. For all three disorders, mRNA therapy restored functional protein to therapeutically relevant levels in target organs, led to sustained and reproducible pharmacology following each dose administration of mRNA, and was well tolerated as supported by liver function tests evaluated in animal models including nonhuman primates. These data provide compelling support for the clinical development of mRNA therapy as a treatment for various rare metabolic disorders.