Therapeutic Options in Hereditary Optic Neuropathies

Abstract

Options for the effective treatment of hereditary optic neuropathies have been a long time coming. The successful launch of the antioxidant idebenone for Leber’s Hereditary Optic Neuropathy (LHON), followed by its introduction into clinical practice across Europe, was an important step forward. Nevertheless, other options, especially for a variety of mitochondrial optic neuropathies such as dominant optic atrophy (DOA), are needed, and a number of pharmaceutical agents, acting on different molecular pathways, are currently under development. These include gene therapy, which has reached Phase III development for LHON, but is expected to be developed also for DOA, whilst most of the other agents (other antioxidants, anti-apoptotic drugs, activators of mitobiogenesis, etc.) are almost all at Phase II or at preclinical stage of research. Here, we review proposed target mechanisms, preclinical evidence, available clinical trials with primary endpoints and results, of a wide range of tested molecules, to give an overview of the field, also providing the landscape of future scenarios, including gene therapy, gene editing, and reproductive options to prevent transmission of mitochondrial DNA mutations.

Clinical Insights into Mitochondrial Neurodevelopmental and Neurodegenerative Disorders: Their Biosignatures from Mass Spectrometry-Based Metabolomics

“…Currently, several agents, such as electron transfer chain function supporter (coenzyme-Q10), energy buffer (creatine), and ROS scavengers (vitamin C, vitamin E, lipoic acid, RP103, and EPI-743) are administered to patients to curtail the ATP deficit due to OXPHOS defects [ 220 ]. Idebenone, a coenzyme Q10 analog with antioxidant properties and increased permeability to the blood–brain barrier, has been shown to improve visual acuity in some patients affected with LHON [ 221 ].…”

Cell Replacement Therapy for Retinal and Optic Nerve Diseases: Cell Sources, Clinical Trials and Challenges

“…The so-called Stem Cell Ophthalmology Treatment Study (SCOTS) and SCOTS-2 (NCT01920867 and NCT03011541) are especially deserving of interest. They are considered the largest stem cell studies for ocular diseases [90]. The research subjects include dominant optic atrophy and LHON.…”

Exploiting hiPSCs in Leber's Hereditary Optic Neuropathy (LHON): Present Achievements and Future Perspectives

“…Effective means that therapy should be able to tangibly modify the disease natural history either by aborting or reverting the catastrophic wave of cell death, or at least limiting the progression so that the visual function is substantially preserved based on anatomical RGCs measurable sparing. Multiple clinical trials have been conducted in recent years, essentially targeting the main pathways involved in the pathogenic mechanism ( 63 ). Several antioxidants molecules, some of which with direct effects on mitochondrial respiration, have been tested in patients: idebenone, Coenzyme Q10 (CoQ10), EPI-743, Elamipretide, curcumin ( 63 ).…”

“…Multiple clinical trials have been conducted in recent years, essentially targeting the main pathways involved in the pathogenic mechanism ( 63 ). Several antioxidants molecules, some of which with direct effects on mitochondrial respiration, have been tested in patients: idebenone, Coenzyme Q10 (CoQ10), EPI-743, Elamipretide, curcumin ( 63 ).…”

“…Besides pharmacological clinical trials, encouraging results are nowadays being reported by clinical trials with gene therapy for patients carrying the m.11778G>A/ MT-ND4 mutation [reviewed in Amore et al ( 63 )], using the Adeno-Associated Virus (AAV)-mediated allotopic expression of a wild-type recoded version of the mtDNA-encoded ND4 subunit of complex I ( 71 , 72 ). To better refine the efficiency of allotropic expression strategy in the context of RGCs, detailing the mitochondrial import of wild-type ND4 protein, its competition with the endogenously expressed mutant ND4, and finally the dynamics of complex I assembly of either one or the other ND4 subunits, may greatly benefit of 3D organoid modeling of LHON.…”