Abstract: Dear editor,
Dysregulated inflammatory responses primarily account for damage to the central nervous system, however, neurodegenerative processes likely contribute to the pathophysiology of progressive forms of multiple sclerosis (MS). These pathophysiological aspects include axonal energy depletion and impaired remyelination capacity (Levin et al., 2014). The clinical efficacy of most disease-modifying therapies in MS to date has been achieved by targeting functions of the adaptive immune system (Cree et al., 2019; Szepanowski et al., 2021). In light of the unmet need for a regenerative therapy in multiple sclerosis, the concept of high-dose biotin (HDB) treatment (approximately 10,000-fold the recommended daily allowance) as a neurometabolic modulator arose (Sedel et al., 2016). Biotin is an essential cofactor for five carboxylase enzymes: pyruvate carboxylase, propionyl-coenzyme A (CoA) carboxylase, 3-methylcrotonyl-CoA carboxylase and two isoforms of acetyl-CoA carboxylase (ACC), ACC-265 and ACC-280 (Zempleni and Kuroishi, 2012). Given the involvement of these carboxylases in a wide range of metabolic pathways, it has been hypothesized that supraphysiological doses of biotin might have neuroprotective and regenerative potential. For example, HDB might contribute to adenosine triphosphate production by increasing intermediates of the tricarboxylic acid cycle and may improve remyelination by elevating levels of the ACC product, malonyl-CoA, as a building block for fatty acid synthesis (Sedel et al., 2016). However, these claims regarding the presumptive mode of action of HDB have barely been validated in preclinical studies employing appropriate animal models. Nevertheless, an open-label pilot study investigating the efficacy of HDB in patients with primary and secondary progressive MS revealed promising results (Sedel et al., 2015). A randomized, double-blind, placebo controlled study (MS-SPI) indicated that HDB might reverse disability in a subgroup of progressive MS patients compared to the placebo arm (Tourbah et al., 2016). Despite these initial positive results, the subsequent phase 3 trial (SPI2) did not show significant improvements of disability, leading to the conclusion that HDB cannot be recommended for patients with progressive forms of MS (Cree et al., 2020).