Advancing a novel experimental mRNA-based therapy for Classic Galactosemia

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PROJECT SUMMARY / ABSTRACT Hereditary deficiency of galactose-1-phosphate uridylyltransferase (GALT, E.C. 2.7.7.12) activity in humans can lead to a potentially lethal disease called Classic Galactosemia (OMIM 230400). Despite the life-saving consequences of newborn screening, early diagnosis, and a galactose-restricted diet, many patients with Classic Galactosemia suffer later in life from complications including growth, neuropsychological, and speech delays as well as primary ovarian insufficiency (POI). There are currently no satisfactory treatments available to prevent/alleviate any of these complications. The precise pathogenic mechanisms of these complications remain unclear, although aberrant galactosylation of glycoproteins/lipids and inositol phospholipid signaling caused by the chronic exposure to toxic intermediates of the blocked galactose metabolic pathway in susceptible tissues have been proposed. But regardless of the proposed mechanisms and any of the associated controversies, no one will debate that the root cause for the disease is the deficiency of GALT enzyme activity in the affected tissues. Therefore, we collaborated with colleagues at Moderna Inc. to explore if we could augment functional GALT activity in an animal model of Classic Galactosemia with an innovative GALT mRNA therapy. Specifically, we hypothesize that targeted augmentation of hepatic GALT activity by GALT mRNA therapy is sufficient to restore whole-body galactose metabolism and ameliorate the disease-relevant phenotypes in Classic Galactosemia. Preliminary results showed that intravenous injection of human GALT mRNA in GalT-/- mice resulted in hepatic expression of active, long-lasting GALT enzyme, which rapidly and effectively reduced gal-1P in liver and some other peripheral tissues and significantly lowered plasma galactose. Yet, it is too early to tell if biomarker correction can lead to actual phenotypic improvements. Therefore, we aim to demonstrate in this application that sole augmentation of hepatic GALT activity in a mouse model of Galactosemia is sufficient to ameliorate the disease-relevant phenotypes (Aim 1) and restore normal whole-body galactose metabolism (oxidation) (Aim 2). If we are successful, we will be able to advance this experimental mRNA therapy to clinical trials (high reward), and this could bring an innovative therapy to address the unmet medical needs of the patients - a high-impact outcome. Moreover, the critical information about the optimal timing of treatment and predictive values of the biomarkers to be revealed in the proposed work will render significant insights to the disease process and guide the development of other modalities, including gene therapy. Last but not least, if we can show that restoration of galactose metabolism in the liver can result in significant improvement of whole-body galactose oxidation, this could lead to diet relaxation (high impact) and such therapeutic strategy could be applied to other metabolic diseases at which targeted therapy is preferred (wide impact).