Experimental Galactose-1-Phosphate Uridylyltransferase (GALT) mRNA Therapy Improves Motor-Related Phenotypes in a Mouse Model of Classic Galactosemia—A Pilot Study

<b>Background:</b> Despite life-saving newborn screening programs and a life-long galactose-restricted diet, many patients with classic galactosemia continue to develop long-term debilitating neurological deficits, speech dyspraxia, and primary ovarian insufficiency (POI). In an earlier study, we showed that administration of an experimental human <i>GALT</i> mRNA predominantly expressed in the liver of the <i>GalT</i> gene-trapped mouse model augmented the expression of hepatic GALT activity, which reduced build-up of galactose and its toxic metabolites not only in the liver but also in the peripheral tissues. Moreover, we showed that the administration of <i>GALT</i> mRNA in the mutant mice restored whole-body galactose oxidation (WBGO), which is a functional biomarker. <b>Methods:</b> In this pilot study, we extended our proof-of-concept efficacy studies to a disease-relevant phenotype: motor impairment. <i>GalT</i>-KO mice aged 3 and 6 weeks old administered biweekly intravenous injections of 100 µL <i>GALT</i> mRNA at a dose of 2 mg/kg for 2 months. Motor performance was assessed using rotarod testing and composite phenotype scoring, 3 and 9 weeks following the dosing regimen. <b>Results:</b> Preliminary results showed that a biweekly dosing at 2 mg/kg for 2 months improved the motor performance of the animals in rotarod and composite phenotype scoring tests in a short-term experiment. <b>Conclusions:</b> Despite being a small-scale study, our findings suggest that when treated early in life, the experimental GALT mRNA is effective in improving the motor-related phenotypes in <i>GalT</i>-KO mice using the specified dosing regimen. These findings highlight the potential of mRNA-based therapies for mitigating neurological symptoms in Classic galactosemia.