Novel Mitochondria-Targeted Therapeutics: Ocular and Neurodegenerative Diseases

Mitochondrial dysfunction is a shared, druggable driver across ocular diseases (glaucoma, age-related macular degeneration, inherited optic neuropathies, diabetic retinopathy) and neurodegenerative disorders (e.g., Parkinson’s, Alzheimer’s, ALS, degenerative features in Multiple Sclerosis). The retina and optic nerve provide a uniquely accessible CNS window where mitochondrial metabolism can be imaged non-invasively and modulated locally, enabling rigorous pharmacology and translational readouts. Converging advances—single-cell multi-omics, live metabolic imaging, mitophagy/quality-control assays, and targeted delivery—have expanded the therapeutic landscape: NAD+ augmentation, sirtuin/PGC-1α network activation, ETC complex modulators, cardiolipin stabilizers, mPTP regulators, redox modulators, and mitochondria-penetrating peptides/nanocarriers.This Research Topic prioritizes studies that bridge preclinical insight to human relevance: target engagement, PK/PD, biomarker development, patient stratification, and early clinical signals:Key Themes and Subtopicso Validation of mitochondrial targets in human ocular/CNS tissues or models (iPSC-derived retinal cells, RPE, retinal ganglion cells; patient-derived neurons and organoids)o Mechanistic pathways: ETC complexes, mitochondrial dynamics (fission/fusion), mitophagy/UPRmt, mPTP, ferroptosis and lipid remodeling (cardiolipin), ER–mitochondria contact sites, neuroinflammation–metabolism couplingo Small molecules, peptide therapeutics, gene/RNA-based strategies (AAV, base/prime editing for mitochondrial genes), and metabolic rewiring approacheso PK/PD modeling for ocular and CNS compartments; distribution across blood–retina and blood–brain barriers; intravitreal, suprachoroidal, periocular, and systemic delivery strategieso Target engagement assays: mitochondrial localization, functional rescue, dose–response, exposure–response relationships in relevant tissueso Human iPSC/organoid co-culture systems capturing neuron–glia–retinal pigment epithelium–vascular interactions; microphysiological systems and retinal-on-a-chipo In vivo models with back-translation to human endpoints: glaucoma, optic neuropathies, age-related macular degeneration, diabetic rethinopathy, synucleinopathies/amyloidopathies with retinal endophenotypeso High-throughput, high-content mitochondrial phenotyping and live-cell metabolic assays; assay controls and standardization to reduce confoundso Clinical studies of mitochondrial-targeted therapies in ocular and neurodegenerative indications; safety pharmacology, phototoxicity, mitochondrial genotoxicity, and off-target metabolic liabilitieso Precision medicine: genetic/omic stratifiers (e.g., OPA1, POLG, mtDNA haplogroups), imaging-defined subtypes, metabolic phenotypes for enrichment Topic editors: Federica Ferrari, Samir Ranjan Panda, Murli Mishra Source: https://www.frontiersin.org/research-topics/77235/novel-mitochondria-targeted-therapeutics-ocular-and-neurodegenerative-diseases