Systemic mRNA Therapy for the Treatment of Fabry Disease: Preclinical Studies in Wild-Type Mice, Fabry Mouse Model, and Wild-Type Non-human Primates

Abstract

Fabry disease is an X-linked lysosomal storage disease caused by loss of alpha galactosidase A (a-Gal A) activity and is characterized by progressive accumulation of globotriaosylceramide and its analogs in all cells and tissues. Although enzyme replacement therapy (ERT) is considered standard of care, the long-term effects of ERT on renal and cardiac manifestations remain uncertain and thus novel therapies are desirable. We herein report preclinical studies evaluating systemic messenger RNA (mRNA) encoding human a-Gal A in wild-type (WT) mice, a-Gal A-deficient mice, and WT non-human primates (NHPs). The pharmacokinetics and distribution of h-a-Gal A mRNA encoded protein in WT mice demonstrated prolonged half-lives of a-Gal A in tissues and plasma. Single intravenous administration of h-a-Gal A mRNA to Gla-deficient mice showed dose-dependent protein activity and substrate reduction. Moreover, long duration (up to 6 weeks) of substrate reductions in tissues and plasma were observed after a single injection. Furthermore, repeat i.v. administration of h-a-Gal A mRNA showed a sustained pharmacodynamic response and efficacy in Fabry mice model. Lastly, multiple administrations to non-human primates confirmed safety and translatability. Taken together, these studies across species demonstrate preclinical proof-of-concept of systemic mRNA therapy for the treatment of Fabry disease and this approach may be useful for other lysosomal storage disorders.

The Ckd. Qld fabRy Epidemiology (aCQuiRE) study protocol: identifying the prevalence of Fabry disease amongst patients with kidney disease in Queensland, Australia

“…However, after controlling for male sex and high urinary protein excretion (which are predictive factors for faster progression to ESRD, changes at 24 months were similar to patients receiving ERT as published in Warnock, et al [62]. Preclinical studies investigating systemic messenger RNA (mRNA) in mice and non-human primates support proof of concept for treatment of Fabry disease [63]. A multi-centre, phase I clinical trial of gene transfer therapy in men with FD (classical phenotype) has also been commenced [64].…”

Neutralising anti‐drug antibodies in Fabry disease can inhibit endothelial enzyme uptake and activity

“…Due to the intra‐ and inter‐individual diversity of antibodies, a comprehensive method using fluorescence‐labelled AGAL combined with intracellular enzymatic activity measurements and ELISA‐based quantification might be the best tool to determine all potential effects of ADAs in individual patients. Furthermore, future studies are now warranted to analyse if either epitope masking or a systemic mRNA therapy may increase therapy efficiency by preventing ADAs from binding and neutralisation.…”

Nanomedicines to Deliver mRNA: State of the Art and Future Perspectives

“…The therapeutic IVT mRNA encodes a missing or down-expressed protein responsible for the disease and associated with genomic defects. These are, for instance, the cases of hemophilia B, characterized by coagulation defects, due to lack of coagulation factor IX [206]; Fabry disease, associated with a deficit of alpha-galactosidase A [207]; methylmalonic acidemia (MMA), caused by methylmalonyl-coenzyme A mutase (MUT) deficiency [208]; propionic acidemia (PA), triggered by a deficiency in the mitochondrial enzyme propionyl-CoA carboxylase [209]; acute intermittent porphyria (AIP), resultant from insufficiency of porphobilinogen deaminase [210]; ornithine transcarbamylase (OTC) deficiency [211]; cystic fibrosis [212] provoked by a genetic defect in the cystic fibrosis transmembrane conductance regulator (CFTR); or William-Beuren syndrome (WBS), which is related to microdeletion of approximately 26 to 28 genes on chromosome 7q11.23, including the elastin gene [204]. Nevertheless, IVT mRNA protein replacement is also useful in disease conditions that are not directly associated with a genetic defect.…”