Abstract:Leber hereditary optic neuropathy (LHON) is a mitochondrial disease leading to optic atrophy due to degeneration of the retinal ganglion cell. A curative treatment is not available at the moment, but a new antioxidant drug, Idebenone, is expected to reduce the progression of the disorder. Two male patients, genetically confirmed with LHON, were clinically, morphologically, and electrophysiologically evaluated, before and three, six, nine and 12 months after starting the treatment. The patient with 3460G>A muta… Show more
“…In vitro, IDE, displays vigorous antioxidant activity by facilitating electrons flux through the mitochondrial electron transport chain, thus leading to increased production of ATP [205,206]. Therefore, IDE has been used in mitochondria-related diseases such as Leber hereditary optic neuropathy (LHON) [207,208] and for the treatment of hereditary myopathies [209]. IDE was shown to activate the NRF2 signalling pathway by promoting its nuclear translocation after H 2 O 2 treatment by using an in vitro model of a human retinal pigment epithelium (RPE) cell line [210].…”
Friedreich’s ataxia (FRDA) is an autosomal, recessive, inherited neurodegenerative disease caused by the loss of activity of the mitochondrial protein frataxin (FXN), which primarily affects dorsal root ganglia, cerebellum, and spinal cord neurons. The genetic defect consists of the trinucleotide GAA expansion in the first intron of FXN gene, which impedes its transcription. The resulting FXN deficiency perturbs iron homeostasis and metabolism, determining mitochondrial dysfunctions and leading to reduced ATP production, increased reactive oxygen species (ROS) formation, and lipid peroxidation. These alterations are exacerbated by the defective functionality of the nuclear factor erythroid 2-related factor 2 (NRF2), a transcription factor acting as a key mediator of the cellular redox signalling and antioxidant response. Because oxidative stress represents a major pathophysiological contributor to FRDA onset and progression, a great effort has been dedicated to the attempt to restore the NRF2 signalling axis. Despite this, the beneficial effects of antioxidant therapies in clinical trials only partly reflect the promising results obtained in preclinical studies conducted in cell cultures and animal models. For these reasons, in this critical review, we overview the outcomes obtained with the administration of various antioxidant compounds and critically analyse the aspects that may have contributed to the conflicting results of preclinical and clinical studies.
“…In vitro, IDE, displays vigorous antioxidant activity by facilitating electrons flux through the mitochondrial electron transport chain, thus leading to increased production of ATP [205,206]. Therefore, IDE has been used in mitochondria-related diseases such as Leber hereditary optic neuropathy (LHON) [207,208] and for the treatment of hereditary myopathies [209]. IDE was shown to activate the NRF2 signalling pathway by promoting its nuclear translocation after H 2 O 2 treatment by using an in vitro model of a human retinal pigment epithelium (RPE) cell line [210].…”
Friedreich’s ataxia (FRDA) is an autosomal, recessive, inherited neurodegenerative disease caused by the loss of activity of the mitochondrial protein frataxin (FXN), which primarily affects dorsal root ganglia, cerebellum, and spinal cord neurons. The genetic defect consists of the trinucleotide GAA expansion in the first intron of FXN gene, which impedes its transcription. The resulting FXN deficiency perturbs iron homeostasis and metabolism, determining mitochondrial dysfunctions and leading to reduced ATP production, increased reactive oxygen species (ROS) formation, and lipid peroxidation. These alterations are exacerbated by the defective functionality of the nuclear factor erythroid 2-related factor 2 (NRF2), a transcription factor acting as a key mediator of the cellular redox signalling and antioxidant response. Because oxidative stress represents a major pathophysiological contributor to FRDA onset and progression, a great effort has been dedicated to the attempt to restore the NRF2 signalling axis. Despite this, the beneficial effects of antioxidant therapies in clinical trials only partly reflect the promising results obtained in preclinical studies conducted in cell cultures and animal models. For these reasons, in this critical review, we overview the outcomes obtained with the administration of various antioxidant compounds and critically analyse the aspects that may have contributed to the conflicting results of preclinical and clinical studies.
“…We read with interest the article by Mercuţ et al about two patients with Leber's hereditary optic neuropathy (LHON), a 15-year-old male carrying the mitochondrial deoxyribonucleic acid (mtDNA) m.3460G>A variant in MT-ND1 [patient (1)] and an 11-year-old male carrying the m.11778G>A variant in MT-ND4 [patient (2)], in whom the morphological and functional response to Idebenone treatment was monitored in three months intervals over a period of one year [1]. Patient (1) experienced improvement of visual acuity, visual fields defects, and visually evoked potentials (VEPs) but no improvement was found regarding the retinal abnormalities, while patient (2) experienced neither functional nor morphological improvement of his abnormalities [1]. The study is appealing but raises concerns that should be discussed.…”
Section: Dear Editormentioning
confidence: 99%
“…The study is appealing but raises concerns that should be discussed. A limitation of the study is that heteroplasmy rates of the causative mtDNA variants were not provided [ 1 ]. Knowing heteroplasmy rates is crucial as they may contribute to the phenotypic expression of mtDNA variants and could be responsible for the variable treatment responses of the two index patients.…”
We read with interest the letter [1] from Josef Finsterer & Sounira Mehri about our article regarding the morphological and functional response to Idebenone therapy in patients with Leber hereditary optic neuropathy (LHON), where two pediatric patients, genetically confirmed, were periodically followed-up over a period of one year after we initiated the treatment [2]. We thank them for the interest shown in this topic and we want to answer the questions they have formulated regarding our study.The first concern was the fact that the heteroplasmy rates of the causative mitochondrial deoxyribonucleic acid (mtDNA) were not provided in our study.
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