High‐dose biotin restores redox balance, energy and lipid homeostasis, and axonal health in a model of adrenoleukodystrophy

Abstract

Biotin is an essential cofactor for carboxylases that regulates the energy metabolism. Recently, high‐dose pharmaceutical‐grade biotin (MD1003) was shown to improve clinical parameters in a subset of patients with chronic progressive multiple sclerosis. To gain insight into the mechanisms of action, we investigated the efficacy of high‐dose biotin in a genetic model of chronic axonopathy caused by oxidative damage and bioenergetic failure, the Abcd1− mouse model of adrenomyeloneuropathy. High‐dose biotin restored redox homeostasis driven by NRF‐2, mitochondria biogenesis and ATP levels, and reversed axonal demise and locomotor impairment. Moreover, we uncovered a concerted dysregulation of the transcriptional program for lipid synthesis and degradation in the spinal cord likely driven by aberrant SREBP‐1c/mTORC1signaling. This resulted in increased triglyceride levels and lipid droplets in motor neurons. High‐dose biotin normalized the hyperactivation of mTORC1, thus restoring lipid homeostasis. These results shed light into the mechanism of action of high‐dose biotin of relevance for neurodegenerative and metabolic disorders.

Safety and efficacy of MD1003 (high-dose biotin) in patients with progressive multiple sclerosis (SPI2): a randomised, double-blind, placebo-controlled, phase 3 trial

“…Relapses occurred in 8•8% (29/331) MD1003 group and 10•0% (31/311) of the placebo. In total 20 adjudicated relapses occurred in the MD1003 group and 25 in the placebo group resulting in an annualized relapse rate of 0•036 and 0•048, respectively (Figure S12-S13, appendix page [19][20].…”

Peroxisomal ABC Transporters: An Update

“…Although no cerebral phenotype is observed, Abcd1 knock-out mice can be considered a physiological model of AMN or female myelopathy and can be useful for screening pharmaceutical compounds. Several molecules have thus been tested and have demonstrated their efficacy, including antioxidant compounds that have been proven to reverse oxidative stress in vitro and reduce locomotor impairment [ 133 , 134 , 135 ]. These hopeful results led to a prospective phase II pilot study that was carried out for 13 AMN patients treated with a cocktail of antioxidant molecules [ 93 ].…”

Modulation of mitochondrial and inflammatory homeostasis through RIP140 is neuroprotective in an adrenoleukodystrophy mouse model

“…Loss of RIP140 on the genetic background of Abcd1 − mice preserved mitochondrial DNA (mtDNA) levels (Figure 3A) and the mRNA expression of mitochondrial biogenesis‐associated genes in the spinal cord (sirtuin 1, Sirt1 ; peroxisome proliferator‐activated receptor, gamma, co‐activator 1‐alpha, Ppargc1a; peroxisome proliferator‐activated receptor gamma, Pparg ; transcription factor A, mitochondrial, Tfam ; and nuclear respiratory factor 1, Nrf1 ) (Figure 3B). The modest decrease of the mitochondrial biogenesis factors and the mtDNA copy numbers in Abcd1 − mice is consistent with a mild, chronic progressive axonopathy, and has been shown repeatedly and robustly reduced in the Abcd1 − mice in all cohorts tested over a 10‐year span [21,26,27,30]. A lack of RIP140 also preserved the protein levels of NDUFB8 [NADH dehydrogenase (ubiquinone) 1 beta subcomplex 8] and SDHB [succinate dehydrogenase complex, subunit B, iron sulphur (Ip)], which are complex I and complex II subunits, respectively, in the spinal cords of Abcd1 − / Rip140 −/− mice (Figure 3C).…”

“…We have previously reported different treatments that have worked successfully in X-ALD mice, all of them based on modulating redox and inflammatory therapeutic targets, shown to be dysregulated after applying multiomics approaches [28,29]. These therapeutic strategies include a combination of high-dose antioxidants [24], the PPARγ agonist pioglitazone [26], SIRT1 activators like resveratrol [27], the UPR inhibitor TUDCA [49], the NRF2 activator dimethyl fumarate [30], and lately high-dose biotin (MD1003) [21]. Some of them have been tested in clinical trials, such as MD1003, a natural derivative of pioglitazone, or the combination of antioxidants, the latter with encouraging results [41].…”

“…The precise role of VLCFAs in X-ALD pathogenesis and the factors that account for the diverse clinical phenotypes and prognosis remain elusive. Redox imbalance, energy metabolism failure, mitochondrial malfunction, and inflammation are common features of most neurodegenerative disorders [19] They also play an early and major role in the pathophysiology of X-ALD [20][21][22][23][24][25][26]. A mouse model of X-ALD (Abcd1 À mice) and cerebral ALD patients share a similar transcriptional signature characterised by dysregulated mitochondrial biogenesis, a pathway controlled by the SIRT1/PGC-1A/PPARG axis [26,27], and chronic inflammation, among other pathway alterations [28].…”