Towards a therapy for mitochondrial disease: an update

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probucol 2 endocrinologydiseasesdrugs
lactic acidosis 1 endocrinologydiseases
mitochondrial disease 18 endocrinologydiseases

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probucol 7684 cellular ATP levels [[12]]. Similarly, inhibition of translation by mTORC1 inhibitors rapamycin and probucol , and by cycloheximide partially rescued the clinical and/or biochemical phenotypes of different models
probucol 16778 mitochondrial function was observed [[30]]. An additional study showed that in zebrafish the antioxidant probucol rescued embryo developmental delay induced by complex I inhibition with rotenone and complex V inhibition
Select Disease Character Offset Disease Term Instance
lactic acidosis 5077 optic neuropathy; Tk2, thymidine kinase 2 deficiency; MELAS, mitochondrial myopathy, encephalopathy, lactic acidosis , stroke-like episodes; PS, Pearson syndrome; Red arrow, gene therapy; Green arrow, drug approval process;
mitochondrial disease 61 Title: Biochemical Society TransactionsTowards a therapy for mitochondrial disease : an updateCaterina GaroneCarlo ViscomiMRC-Mitochondrial Biology Unit, Cambridge CB2 0XY, U.K.Publication
mitochondrial disease 303 10/2018Publication date (epub): 10/2018AbstractPreclinical work aimed at developing new therapies for mitochondrial disease s has recently given new hopes and opened unexpected perspectives for the patients affected by these
mitochondrial disease 1030 dynamic research field.IntroductionThe extreme genetic, biochemical, and clinical complexity of primary mitochondrial disease s challenges both clinical and research activity in the field. Mutations in any of the mitochondrial
mitochondrial disease 2522 mutations, such in LHON (Leber's hereditary optic neuropathy) disease. LHON is one of the most frequent mitochondrial disease s and is due to homoplasmic mutations in mtDNA leading to blindness. The non-synonymous mutations at
mitochondrial disease 4624 clinical and drug approval stages are represented in the figure. Note the lack of preclinical data in mitochondrial disease models for some new or re-purpose therapies. Treatments are also divided into ‘general action' or
mitochondrial disease 5697 biogenesis (Figure 2) [[7]]. The idea of using rapamycin, a widely used mTORC1 inhibitor, to treat mitochondrial disease s stemmed from the observation that inhibiting cytosolic translation significantly prolonged (approximately
mitochondrial disease 9355 lactate, pyruvate, and β-hydroxybutyrate [[16]].Notably, rapamycin was beneficial in all the models of mitochondrial disease tested, independently of the genetic lesion. Although the mechanism ultimately mediating rapamycin-dependent
mitochondrial disease 10169 with different mechanisms of action on mTORC1 are being developed [[17]], but have not been tested on mitochondrial disease models. Given the broad effects of mTOR inhibition, including immunosuppressive action, side effects
mitochondrial disease 14724 [[25]].OutlookThe fascinating results on the Ndufs4 KO mouse await confirmation in additional models of mitochondrial disease . In addition, the mechanistic details are still unclear since hypoxia is likely to act at different
mitochondrial disease 15428 them.Reducing ROS: between hopes and risksRationaleAntioxidants are routinely used in the therapy of mitochondrial disease s under the assumption that increased ROS-related damage is a component of the pathogenesis. However,
mitochondrial disease 17451 trials, such as RTA408, idebenone, thioctic (lipoic) acid, EPI-743, KH176, are ongoing on different mitochondrial disease s (Figure 1). However, with the exception of KH176, none of these studies was supported by rigorous preclinical
mitochondrial disease 18010 chronic patients [[34]].OutlookAntioxidants are probably the most widely used drugs in the therapy of mitochondrial disease s. However, there is accumulating evidence that antioxidants may also be detrimental in some conditions
mitochondrial disease 22299 biogenesisRationaleSince bioenergetic defects and reduced ATP synthesis play major roles in the pathogenesis of mitochondrial disease , increasing mitochondrial mass and/or activity can, in principle, be beneficial. The stimulation of
mitochondrial disease 22502 The stimulation of mitochondrial biogenesis is regarded as one of the most promising approaches for mitochondrial disease [[42],[43]].ResultsPositive results have been reported on several mouse models using the AMPK agonist
mitochondrial disease 26143 into the cells. In addition, liver transplant has also been proposed as a suitable therapy for other mitochondrial disease s with hepatopathy, such as Alpers disease, provided that the clinical conditions are not too severe
mitochondrial disease 34069 been provided. However, several clinical trials with elamipretide are currently ongoing for primary mitochondrial disease , primary mitochondrial myopathy, and LHON. Only for one of them (NCT02367014), aimed at providing evidence
mitochondrial disease 38576 a systematic literature review, Rahman et al. identified 35 natural history studies encompassing 28 mitochondrial disease entities. Data from those studies have helped to redefine diagnostic criteria for classical clinical
mitochondrial disease 39465 clinical trial readiness in mitochondrial disorders [[88]].ConclusionsThe development of new therapies for mitochondrial disease s is moving fast at the preclinical level, but the clinical translation is lagging behind. The only treatment

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