Pre-clinical evaluation of cysteamine bitartrate as a therapeutic agent for mitochondrial respiratory chain disease

Abstract

Cysteamine bitartrate is a US Food and Drug Administration-approved therapy for nephropathic cystinosis also postulated to enhance glutathione biosynthesis. We hypothesized this antioxidant effect may reduce oxidative stress in primary mitochondrial respiratory chain (RC) disease, improving cellular viability and organismal health. Here, we systematically evaluated the therapeutic potential of cysteamine bitartrate in RC disease models spanning three evolutionarily distinct species. These pre-clinical studies demonstrated the narrow therapeutic window of cysteamine bitartrate, with toxicity at millimolar levels directly correlating with marked induction of hydrogen peroxide production. Micromolar range cysteamine bitartrate treatment in Caenorhabditis elegans gas-1(fc21) RC complex I (NDUFS2 −/− ) disease invertebrate worms significantly improved mitochondrial membrane potential and oxidative stress, with corresponding modest improvement in fecundity but not lifespan. At 10 to 100 μm concentrations, cysteamine bitartrate improved multiple RC complex disease FBXL4 human fibroblast survival, and protected both complex I (rotenone) and complex IV (azide) Danio rerio vertebrate zebrafish disease models from brain death. Mechanistic profiling of cysteamine bitartrate effects showed it increases aspartate levels and f lux, without increasing total glutathione levels. Transcriptional normalization of broadly dysregulated intermediary metabolic, glutathione, cell defense, DNA, and immune pathways was greater in RC disease human cells than in C. elegans, with similar rescue in both models of downregulated ribosomal and proteasomal pathway expression. Overall, these data suggest 1838

Therapeutic Approaches to Treat Mitochondrial Diseases: “One-Size-Fits-All” and “Precision Medicine” Strategies

“…Therefore, cysteamine increases the glutathione precursor cysteine availability, raising the possibility of its repositioning as a drug for PMD. A recent study evaluated cysteamine bitartrate’s therapeutic potential in three different models of mitochondrial disorders: C. elegans model of CI defect, FBXL4 mutant human fibroblast, and zebrafish models of pharmacologically-induced CI and CIV defects [ 192 ]. Although a therapeutic potential has been observed, no evident modulation of total glutathione levels was reported, raising concerns about its application in MRC diseases [ 192 ].…”

Mitochondrial Dynamics of Proximal Tubular Epithelial Cells in Nephropathic Cystinosis

“…cAMP, in fact, is one of the major regulators of mitochondrial function [28][29][30] and dynamics [31]. In this contest, it should be noted that MEA has been found to improve mitochondrial function in mitochondrial respiratory chain diseases [32]. Mitochondrial dynamics is balanced between rates of fusion and fission that respond to pathophysiologic signals.…”

Clinical trials in mitochondrial disorders, an update

“…Cysteamine bitartrate is an aminothiol used as an approved therapy for nephropathic cystinosis [ 19 ]. Cysteamine breaks the disulfide bond of cystine, forming cysteine–cysteamine disulfide and cysteine, the latter of which is a precursor of glutathione biosynthesis [ 20 , 21 ]. Thus, a delayed release form of cysteamine bitartrate was repurposed and used as RP103 in an open label, dose-escalating study to assess its safety and efficacy in children with mitochondrial diseases.…”