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Mitochondrial Dysfunction and Barth Syndrome
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
Arianna F. Anzmann, Steven M. Claypool, Hilary Vernon
In terms of small molecule/drug therapies for BTHS (Figure 4), there is an ongoing clinical trial testing the safety, tolerability, and efficacy of Elamipretide in Barth Syndrome sponsored by Stealth BioTherapeutics Inc. (ClinicalTrials.gov Identifier: NCT03098797)167. Elamipretide, also known as SS-31 (D-Arg-dimethylTyr-Lys-Phe-NH2), was first developed in 2004 by Zhao et al. as part of a series of peptide antioxidants, Szeto-Schiller peptides (SS peptides), that are targeted to the mitochondrion and concentrated in the IMM168. Since its development, it has been reported that SS-31 binds with high affinity to CL and that the SS-31/CL complex inhibits CL peroxidation by Cyt. C and optimizes OXPHOS169–172. In addition to its therapeutic potential, a greater understanding SS-31’s mechanism of action in improving mitochondrial function may provide insight into the pathophysiology of BTHS.
Mitochondrial Redox Regulation in Adaptation to Exercise
Published in James N. Cobley, Gareth W. Davison, Oxidative Eustress in Exercise Physiology, 2022
Christopher P. Hedges, Troy L. Merry
While there is building evidence of acute exercise-mediated mitochondrial redox signalling, whether this is important in regulating adaptive responses to exercise training has yet to be explored in detail. Tools to specifically examine the causative nature of mitochondrial ROS in exercise are becoming more widely available, and it is expected that this area of research will expand in the coming years. Such tools include mitochondrial-targeted antioxidants Szeto-Schiller-31 (SS31/elamipretide), XJB-5-131, mitoTEMPO, mitochondria-targeted vitamin E and MitoQ (Broome et al., 2018). With the exception of MitoQ, which is available as an over-the-counter supplement in many countries, the use of other mitochondrial-targeted antioxidants has been largely limited to pre-clinical and phase 1/2 clinical trials, perhaps restricting their use in human exercise research. However, the effect of mitochondrial antioxidants in rodents has so far also been limited to a handful of studies. These show SS31 does not greatly effect fatigue of isolated muscle fibres (Katz et al., 2014; Cheng et al., 2015), and the only long-term combined exercise and mitochondrial antioxidant supplementation study in humans showed that MitoQ does not affect improvements in oxidative capacity induced by 3 weeks of endurance training (Shill et al., 2016). Therefore, there is still a lot that is unknown about the effects of targeting mitochondrial ROS in the exercise context. In addition to the use of antioxidant supplements, insights could be gained from the studying of mice with targeted expression or deletion of antioxidants at the mitochondria, such as the mCAT (mitochondrial catalase overexpression) and MnSOD overexpression mice or Prx3 knockout mice. While these mice appear to show acute exercise phenotypes, with mCAT mice having improved exercise capacity (Li et al., 2009) and Prx3 knockout and MnSOD heterozygous knockout mice (Zhang et al., 2016; Kinugawa et al., 2005) have impaired swimming performance with age, how the manipulation of expression of these mitochondrial antioxidants affects exercise training responsiveness has not been examined.
Investigational drugs in clinical trials for macular degeneration
Published in Expert Opinion on Investigational Drugs, 2022
Michael J Tolentino, Andrew J Tolentino
Elamipretide is a cardiolipin-protective small tetrapeptide that targets and protects mitochondrial cristae and promotes oxidative phosphorylation [140]. A phase I open label trial tested subcutaneous Elamipretide in 2 cohort of patients. The first cohort are patients with intermediate AMD with high-risk drusen without GA and a cohort with non-central GA. The outcomes of low luminance visual acuity were assessed at week 24. Patients with non-central GA (n = 15) showed a mean increase in low-luminance visual acuity of 5.4 ± 7.9 letters and BCVA of 4.6 ± 5.1 letters. The patients with high-risk drusen (n = 19) also demonstrated improvements in low luminance and BCVA. Adverse events were mostly limited to reactions in the injection site [141]. A placebo-controlled phase II trial, ReCLAIM-2 is currently enrolling.
Discontinued disease-modifying therapies for Alzheimer’s disease: status and future perspectives
Published in Expert Opinion on Investigational Drugs, 2020
Bruno P. Imbimbo, Madia Lozupone, Mark Watling, Francesco Panza
Mitochondrial dysfunction and oxidative stress increase with aging and are closely linked to neurodegeneration [120]. Mitochondrial dysfunction is an early event in AD pathogenesis and is associated with reduced metabolism, alteration of calcium homeostasis, and increased levels of reactive oxygen species, lipid peroxidation, and apoptosis [121]. Asymptomatic subjects at risk of developing AD show low levels of mitochondrial DNA in CSF [122]. It has been suggested that mitochondrial dysfunction occurs before Aβ deposition and initiates pathologic molecular cascades that promote Aβ accumulation in AD [123]. Several compounds specifically targeting mitochondria are currently being investigated [124]. Elamipretide (SS-31) is an oligopeptide that selectively interacts with cardiolipin on the inner mitochondrial membrane. Studies in transgenic mouse models of AD have shown that it can attenuate mitochondrial dysfunction and enhance synaptic activity [125], suggesting that the drug could be evaluated in AD. Elamipretide is currently being evaluated in clinical trials for rare clinical indications including mitochondrial myopathy, Barth syndrome, Leber hereditary optic neuropathy, and Huntington’s disease. J147, a synthetic derivative of curcumin, has high affinity for the mitochondrial α-F1 subunit of ATP synthase (ATP5A) [126] and has shown promising pharmacological effects in transgenic mouse models of AD [127]. The safety and pharmacokinetics of J147 is currently being evaluate in Phase I study in 64 healthy volunteers (NCT03838185). CP2 is a small organic molecule that crosses the BBB and accumulates in neuronal mitochondria [128]. CP2 competitively occupies the flavin mononucleotide redox site within complex I, a respiratory chain holoenzyme on the mitochondrial inner membrane, thereby inhibiting its function. CP2 has been shown to attenuate cognitive decline in three animal models of AD [128]. However, CP2 has not yet entered clinical trials as further optimization of this compound is being pursued [129].
Should drug discovery scientists still embrace the amyloid hypothesis for Alzheimer’s disease or should they be looking elsewhere?
Published in Expert Opinion on Drug Discovery, 2020
Bruno Pietro Imbimbo, Stefania Ippati, Mark Watling
Mitochondrial dysfunction and oxidative stress increase with aging and are tightly linked to neurodegeneration [55]. AD is associated with dysfunctional mitochondria and an imbalance between pro-oxidants and antioxidants, which in turn, induce oxidative damage to DNA, proteins, and lipids in the brain. Some believe Aβ contributes to AD mitochondrial dysfunction, while others suggest that mitochondrial dysfunction lies upstream of Aβ deposition and initiates pathologic molecular cascades that promote Aβ accumulation in AD [56]. To date, antioxidant agents have not been successful in treating AD [57], partly due to their low bioavailability and poor blood-brain barrier penetration. Agents that specifically target mitochondria to decrease mitochondria-derived reactive oxygen species have been investigated. Methylene blue (methylthioninium chloride) was found to enhance mitochondrial function [58,59] and to induce autophagy [60] but its derivative LMTM failed to show clinical efficacy in 2 large trials both in mild-to-moderate and mild AD [13,14]. CP2 is a small organic molecule that crosses the blood-brain barrier and accumulates in neuronal mitochondria [61]. It competes with flavin mononucleotide in binding to the redox center of complex I, leading to an elevated AMP/ATP ratio and activation of AMP-activated protein kinase in neurons and mouse brain without inducing oxidative damage or inflammation. CP2 was shown to avert cognitive decline in three animal models of AD [61]. However, no clinical trials are ongoing on this interesting molecule. Elamipretide (SS-31) is a mitochondria-targeted tetrapeptide that selectively interacts with cardiolipin on the inner mitochondrial membrane. Studies in APP transgenic mice have shown that elamipretide treatment reduces mitochondrial dysfunction and enhances synaptic activity [62] suggesting that the drug could be active in AD. It is currently being evaluated in clinical trials for rare disease indications including mitochondrial myopathy, Barth syndrome, Leber hereditary optic neuropathy, and Huntington disease.