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.
Mitochondrial optic neuropathies constitute an important cause of chronic visual morbidity and registrable blindness in both the paediatric and adult population. It is a genetically heterogeneous ...group of disorders caused by both mitochondrial DNA (mtDNA) mutations and a growing list of nuclear genetic defects that invariably affect a critical component of the mitochondrial machinery. The two classical paradigms are Leber hereditary optic neuropathy (LHON), which is a primary mtDNA disorder, and autosomal dominant optic atrophy (DOA) secondary to pathogenic mutations within the nuclear gene
OPA1
that encodes for a mitochondrial inner membrane protein. The defining neuropathological feature is the preferential loss of retinal ganglion cells (RGCs) within the inner retina but, rather strikingly, the smaller calibre RGCs that constitute the papillomacular bundle are particularly vulnerable, whereas melanopsin-containing RGCs are relatively spared. Although the majority of patients with LHON and DOA will present with isolated optic nerve involvement, some individuals will also develop additional neurological complications pointing towards a greater vulnerability of the central nervous system (CNS) in susceptible mutation carriers. These so-called “plus” phenotypes are mechanistically important as they put the loss of RGCs within the broader perspective of neuronal loss and mitochondrial dysfunction, highlighting common pathways that could be modulated to halt progressive neurodegeneration in other related CNS disorders. The management of patients with mitochondrial optic neuropathies still remains largely supportive, but the development of effective disease-modifying treatments is now within tantalising reach helped by major advances in drug discovery and delivery, and targeted genetic manipulation.
Many neurodegenerative disorders, such as Parkinson's disease (PD) and Alzheimer's disease (AD), are characterized by loss of retinal ganglion cells (RGCs) as part of the neurodegenerative process. ...Optical coherence tomography (OCT) studies demonstrated variable degree of optic atrophy in these diseases. However, the pattern of degenerative changes affecting the optic nerve (ON) can be different. In particular, neurodegeneration is more evident for magnocellular RGCs in AD and multiple system atrophy with a pattern resembling glaucoma. Conversely, in PD and Huntington's disease, the parvocellular RGCs are more vulnerable. This latter pattern closely resembles that of mitochondrial optic neuropathies, possibly pointing to similar pathogenic mechanisms. In this review, the currently available evidences on OCT findings in these neurodegenerative disorders are summarized with particular emphasis on the different pattern of RGC loss. The ON degeneration could become a validated biomarker of the disease, which may turn useful to follow natural history and possibly assess therapeutic efficacy.
The optic nerve and the cells that give origin to its 1.2 million axons, the retinal ganglion cells (RGCs), are particularly vulnerable to neurodegeneration related to mitochondrial dysfunction. ...Optic neuropathies may range from non-syndromic genetic entities, to rare syndromic multisystem diseases with optic atrophy such as mitochondrial encephalomyopathies, to age-related neurodegenerative diseases such as Alzheimer's and Parkinson's disease where optic nerve involvement has, until recently, been a relatively overlooked feature. New tools are available to thoroughly investigate optic nerve function, allowing unparalleled access to this part of the central nervous system. Understanding the molecular pathophysiology of RGC neurodegeneration and optic atrophy, is key to broadly understanding the pathogenesis of neurodegenerative disorders, for monitoring their progression in describing the natural history, and ultimately as outcome measures to evaluate therapies. In this review, the different layers, from molecular to anatomical, that may contribute to RGC neurodegeneration and optic atrophy are tackled in an integrated way, considering all relevant players. These include RGC dendrites, cell bodies and axons, the unmyelinated retinal nerve fiber layer and the myelinated post-laminar axons, as well as olygodendrocytes and astrocytes, looked for unconventional functions. Dysfunctional mitochondrial dynamics, transport, homeostatic control of mitobiogenesis and mitophagic removal, as well as specific propensity to apoptosis may target differently cell types and anatomical settings. Ultimately, we can envisage new investigative approaches and therapeutic options that will speed the early diagnosis of neurodegenerative diseases and their cure.
Leber's hereditary optic neuropathy (LHON) is a mitochondrial disease characterized by visual loss, and rarely associated with extraocular manifestations including multiple sclerosis‐like lesions. ...The association of LHON and neuromyelitis optica spectrum disorders has rarely been reported. Here is reported a case of glial fibrillary acidic protein astrocytopathy presenting with area postrema syndrome in a patient with previously diagnosed recessive LHON due to mutations in the nuclear gene DNAJC30. This case emphasizes the necessity of extensive investigations for other treatable conditions in patients with LHON and otherwise unexplained extraocular involvement and the possibility that also visual symptoms can respond to immune therapy.
Mitochondrial diseases are caused by both nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) mutations and are characterized by heterogeneous clinical presentations due to the potential affection of ...each organ of the body, in particular those with high energy requirements.
The most common clinical presentations of mitochondrial defects are mitochondrial myopathy, central nervous system manifestations including cerebral, cerebellar, brainstem and spinal cord atrophy, white matter disease, stroke‐like episodes and epilepsy, peripheral neuropathy, optic atrophy, pigmentary retinopathy, sensorineural deafness, cardiomyopathy, diabetes and kidney disorders.
Thus, clinical diagnostic work‐out for mitochondrial disorders should include muscle biopsy, brain MRI with magnetic resonance spectroscopy, electromyography, electroencephalography, ophthalmological evaluation, audiometry, cardiac evaluation including echocardiogram, endocrinological and nephrological evaluation. Laboratory exams may include traditional markers as creatine kinase and lactic acid as well as more recent biomarkers such as GDF‐15 and FGF‐21.
Genetic testing includes both nuclear and mtDNA sequencing based on family history that can point towards a matrilinear or mendelian transmission of the genetic defect. Sporadic cases are also possible and this particularly apply to single mtDNA deletions and nuclear de‐novo mutations. Biochemical analysis of muscle biopsy is also important to evaluate the presence of single/multiple respiratory chain complexes defect.
The most common mitochondrial disorder due to mtDNA mutations is Leber's Hereditary Optic Neuropathy, followed by Mitochondrial Encephalopathy, Lactic Acidosis and Stroke‐like Episodes (MELAS), whereas among the nuclear genes OPA1 gene mutations are the most common cause of Dominant Optic Atrophy.
Reference
La Morgia C, Maresca A, Caporali L, Valentino ML, Carelli V. Mitochondrial diseases in adults. J Intern Med. 2020 Jun;287(6):592–608. doi: 10.1111/joim.13064. PMID: 32463135.
REVERSE is a randomized, double-masked, sham-controlled, multicenter, phase 3 clinical trial that evaluated the efficacy of a single intravitreal injection of rAAV2/2-
in subjects with visual loss ...from Leber hereditary optic neuropathy (LHON). A total of 37 subjects carrying the m.11778G>A (
) mutation and with duration of vision loss between 6 to 12 months were treated. Each subject's right eye was randomly assigned in a 1:1 ratio to treatment with rAAV2/2-
(GS010) or sham injection. The left eye received the treatment not allocated to the right eye. Unexpectedly, sustained visual improvement was observed in both eyes over the 96-week follow-up period. At week 96, rAAV2/2-
-treated eyes showed a mean improvement in best-corrected visual acuity (BCVA) of -0.308 LogMAR (+15 ETDRS letters). A mean improvement of -0.259 LogMAR (+13 ETDRS letters) was observed in the sham-treated eyes. Consequently, the primary end point, defined as the difference in the change in BCVA from baseline to week 48 between the two treatment groups, was not met (
= 0.894). At week 96, 25 subjects (68%) had a clinically relevant recovery in BCVA from baseline in at least one eye, and 29 subjects (78%) had an improvement in vision in both eyes. A nonhuman primate study was conducted to investigate this bilateral improvement. Evidence of transfer of viral vector DNA from the injected eye to the anterior segment, retina, and optic nerve of the contralateral noninjected eye supports a plausible mechanistic explanation for the unexpected bilateral improvement in visual function after unilateral injection.
Abstract
The in vivo role for RNase H1 in mammalian mitochondria has been much debated. Loss of RNase H1 is embryonic lethal and to further study its role in mtDNA expression we characterized a ...conditional knockout of Rnaseh1 in mouse heart. We report that RNase H1 is essential for processing of RNA primers to allow site-specific initiation of mtDNA replication. Without RNase H1, the RNA:DNA hybrids at the replication origins are not processed and mtDNA replication is initiated at non-canonical sites and becomes impaired. Importantly, RNase H1 is also needed for replication completion and in its absence linear deleted mtDNA molecules extending between the two origins of mtDNA replication are formed accompanied by mtDNA depletion. The steady-state levels of mitochondrial transcripts follow the levels of mtDNA, and RNA processing is not altered in the absence of RNase H1. Finally, we report the first patient with a homozygous pathogenic mutation in the hybrid-binding domain of RNase H1 causing impaired mtDNA replication. In contrast to catalytically inactive variants of RNase H1, this mutant version has enhanced enzyme activity but shows impaired primer formation. This finding shows that the RNase H1 activity must be strictly controlled to allow proper regulation of mtDNA replication.
The landmark year 1988 can be considered as the birthdate of mitochondrial medicine, when the first pathogenic mutations affecting mtDNA were associated with human diseases. Three decades later, the ...field still expands and we are not 'scraping the bottom of the barrel' yet. Despite the tremendous progress in terms of molecular characterization and genotype/phenotype correlations, for the vast majority of cases we still lack a deep understanding of the pathogenesis, good models to study, and effective therapeutic options. However, recent technological advances including somatic cell reprogramming to induced pluripotent stem cells (iPSCs), organoid technology, and tailored endonucleases provide unprecedented opportunities to fill these gaps, casting hope to soon cure the major primary mitochondrial phenotypes reviewed here. This group of rare diseases represents a key model for tackling the pathogenic mechanisms involving mitochondrial biology relevant to much more common disorders that affect our currently ageing population, such as diabetes and metabolic syndrome, neurodegenerative and inflammatory disorders, and cancer.
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