Structural insights into DdCBE in action enable high-precision mitochondrial DNA editing
DddA-derived cytosine base editor (DdCBE) couples transcription activator-like effector (TALE) arrays and the double-stranded DNA (dsDNA)-specific cytidine deaminase DddA to target mitochondrial DNA (mtDNA) for editing. However, structures of DdCBE in action are unavailable, impeding its mechanistic-based optimization for high-precision-demanding therapeutic applications. Here, we determined the cryo-electron microscopy (cryo-EM) structures of DdCBE targeting two native mitochondrial gene loci…
Estradiol alleviates disease phenotypes caused by m.3635G > a mutations by activating mitochondrial biogenesis and PINK1-Parkin mediated mitophagy in iPSC-derived retinal pigment epithelium cells
Leber’s hereditary optic neuropathy (LHON), a mitochondrial disorder marked by central vision loss, exhibits incomplete penetrance and male predominance. Since there are no adequate models for understanding the rapid vision loss associated with LHON, we generated induced pluripotent stem cells (iPSCs) from LHON patients carrying the pathogenic m.3635G > A mutation and differentiated them into retinal pigment epithelium (RPE) cells. The mutation disrupted mitochondrial dynamics, suppressing…
MetabOCT: a clinical trial looking for a metabolomic signature predicting the onset of Leber’s hereditary optic neuropathy in healthy MtDNA mutations carriers
CONCLUSION: Identifying pre-clinical biomarkers would open a window for clinical trials.
Quantitative assessment of retinal microvasculature using optical coherence tomography angiography and correlation with visual acuity in leber’s hereditary optic neuropathy
CONCLUSION: LHON is characterized by diffuse impairment of the retinal microvasculature, predominantly affecting the macular region and corresponding to the papillomacular bundle. Furthermore, BCVA demonstrated significant correlations with retinal blood flow and structural parameters.
Metformin may alter the course of Leber’s hereditary optic neuropathy: a case report
Leber’s hereditary optic neuropathy (LHON) is a rare inherited mitochondrial disease caused by variants in mitochondrial DNA (mtDNA) transmitted exclusively through the maternal line. The disease predominantly affects young males and is characterized by progressive bilateral vision loss. Idebenone, a well-studied drug, modestly enhances the mitochondrial function and visual acuity in many patients with LHON. In this study, we report the case of a 48-year-old woman diagnosed with LHON…
Late-onset Leber’s hereditary optic neuropathy and antiandrogens for prostate cancer: is there a causative link?
INTRODUCTION: Leber’s hereditary optic neuropathy (LHON) is a maternally inherited condition due to mitochondrial DNA (mtDNA) mutations usually affecting young men within their thirties, while women seem protected by estrogens with a female-to-male ratio of 1:3. Late-onset cases (over 40 years of age) are usually associated to toxic exposure to tobacco smoke or drugs causing mitochondrial dysfunction.
Developing Intravenous Delivery of Water-Soluble Prodrugs of Idebenone for the Treatment of Acute Ischemic Stroke
Ischemic stroke (IS) represents a substantial global health threat, but only a few effective medicines exist to treat IS, with a huge unmet clinical need. Idebenone (IDB), a coenzyme Q10 analogue, has multitarget effects, including enhancing mitochondrial energy metabolism, scavenging free radicals, and anti-inflammation, which is approved in Europe for treating Leber’s hereditary optic neuropathy (LHON). However, IDB has poor water solubility and oral bioavailability, resulting in insufficient…
Combination treatment with antioxidants and creatine alleviates common and variant-specific mitochondrial impairments in Leber’s hereditary optic neuropathy patient-derived fibroblasts
Leber’s hereditary optic neuropathy (LHON) is characterized by painless and rapidly progressive central vision loss, caused by various mutations in mitochondrial DNA, leading to a high genetic and phenotypic heterogeneity. Currently, the only approved therapy is idebenone, a CoQ10 synthetic analogue, that improved visual acuity in some LHON patients; however, results are highly variable due its dependency on functional NAD(P)H oxidoreductase I (NQO1) protein levels, thus limiting broader…
In Vivo Reprogramming Dysfunctional Retinal Ganglion Cells and Visual-phototransduction via Wireless Charging Nanogold for Leber’s Hereditary Optic Neuropathy
Gene therapy offers a promising treatment for Leber’s hereditary optic neuropathy (LHON), a disease of retinal ganglion cell (RGC) degeneration with severe vision loss caused by mitochondria-NADH dehydrogenase 4 (MT-ND4) mutations. However, optimizing mitochondria-targeted gene delivery to promote RGC regeneration and visual-photoreception recovery remains challenging in LHON. Here, mitochondria-targeted wireless charging gold nanoparticles (WCGs), doubling as a wireless charging-mediated…
Initial Macular Ganglion Cell Changes During Conversion of Leber Hereditary Optic Neuropathy
CONCLUSIONS: Nasal GCC thinning is a reliable early indicator of the conversion from normal vision to visual loss in LHON as demonstrated in 10 of 17 eyes. This pattern of GCC loss provides insights into the disease mechanism and highlights the utility of OCT analysis for early diagnosis. The nasal GCC loss suggests selective vulnerability of ganglion cells serving the foveal region in LHON. Early identification of nasal GCC changes may facilitate timely intervention as gene therapy and other…