Leber hereditary optic neuropathy – Therapeutic challenges and early promise

AbstractLeber hereditary optic neuropathy (LHON) is the most common primary mitochondrial DNA (mtDNA) disorder in the general population. It is an important cause of severe, usually irreversible, visual loss among young adults with a peak age of onset in the second and third decades of life. Management is currently mostly supportive but recent developments in LHON research are pointing the way towards more effective treatments for this blinding mitochondrial disorder

The clinical manifestations and molecular mechanisms of mitrochondrial neuro-opthalmological disorders

Autosomal dominant optic atrophy (DOA) classically presents with bilateral, symmetric visual failure in early childhood, with the pathological hallmark being the selective loss of retinal ganglion cells (RGCs). In the first population-based epidemiological study of DOA, we were able to estimate its minimum prevalence at 1 in 35,000 in the North of England. In independent case series from Northern Europe and North America, the majority of families with DOA harboured pathogenic OPA1 mutations (50.0-57.6%), and large-scale OPA1 rearrangements were present in only a small subgroup (11.1-12.9%). We also confirmed that OPA3 mutations were very rare in non-syndromal DOA cases. Visual deterioration was observed in over half (54.2-67.4%) of all patients during long term follow-up, and the rate of visual decline varied markedly both between and within families. In a large multi-centre study of 104 OPA1-positive patients from 45 independent families, we established that additional neuromuscular complications are common in OPA1 disease, affecting up to 20% of all mutational carriers. Bilateral sensorineural deafness beginning in late childhood and early adulthood was a prominent manifestation, followed by a combination of ataxia, myopathy, peripheral neuropathy and chronic progressive external ophthalmoplegia (CPEO) from the third decade of life onwards. We also identified novel clinical presentations with spastic paraparesis mimicking hereditary spastic paraplegia, and a multiple sclerosis-like illness. Patients with these syndromal disease variants (DOA+) had a worse visual prognosis, and this was associated with a more pronounced reduction in retinal nerve fibre layer thickness compared to patients with pure DOA. Interestingly, there was a two- to three-fold increased risk of developing DOA+ features with missense OPA1 mutations and those located within the GTPase domain.EThOS - Electronic Theses Online ServiceMedical Research Council (UK)GBUnited Kingdo

Disorders of the Optic Nerve in Mitochondrial Cytopathies: New Ideas on Pathogenesis and Therapeutic Targets

Mitochondrial cytopathies are a heterogeneous group of human disorders triggered by disturbed mitochondrial function. This can be due to primary mitochondrial DNA mutations or nuclear defects affecting key components of the mitochondrial machinery. Optic neuropathy is a frequent disease manifestation and the degree of visual failure can be profound, with a severe impact on the patient’s quality of life. This review focuses on the major mitochondrial disorders exhibiting optic nerve involvement, either as the defining clinical feature or as an additional component of a more extensive phenotype. Over the past decade, significant progress has been achieved in our basic understanding of Leber hereditary optic neuropathy and autosomal-dominant optic atrophy—the two classical paradigms for these mitochondrial optic neuropathies. There are currently limited treatments for these blinding ocular disorders and, ultimately, the aim is to translate these major advances into tangible benefits for patients and their families

Genetic variation in the methylenetetrahydrofolate reductase gene, MTHFR, does not alter the risk of visual failure in Leber’s hereditary optic neuropathy

Focal neurodegeneration of the optic nerve in Leber hereditary optic neuropathy (LHON) is primarily due to a maternally inherited mitochondrial DNA mutation. However, the markedly reduced penetrance of LHON and segregation pattern of visual failure within families implicates an interacting nuclear genetic locus modulating the phenotype. Folate deficiency is known to cause bilateral optic neuropathy, and defects of folate metabolism have been associated with nonarteritic ischemic optic neuropathy

Humoral immune responses to AAV gene therapy in the ocular compartment

Viral vectors can be utilised to deliver therapeutic genes to diseased cells. Adeno-associated virus (AAV) is a commonly used viral vector that is favoured for its ability to infect a wide range of tissues whilst displaying limited toxicity and immunogenicity. Most humans harbour anti-AAV neutralising antibodies (NAbs) due to subclinical infections by wild-type virus during infancy and these pre-existing NAbs can limit the efficiency of gene transfer depending on the target cell type, route of administration and choice of serotype. Vector administration can also result in de novo NAb synthesis that could limit the opportunity for repeated gene transfer to diseased sites. A number of strategies have been described in preclinical models that could circumvent NAb responses in humans, however, the successful translation of these innovations into the clinical arena has been limited. Here, we provide a comprehensive review of the humoral immune response to AAV gene therapy in the ocular compartment. We cover basic AAV biology and clinical application, the role of pre-existing and induced NAbs, and possible approaches to overcoming antibody responses. We conclude with a framework for a comprehensive strategy for circumventing humoral immune responses to AAV in the future

From Transcriptomics to Treatment in Inherited Optic Neuropathies.

Inherited optic neuropathies, including Leber Hereditary Optic Neuropathy (LHON) and Dominant Optic Atrophy (DOA), are monogenetic diseases with a final common pathway of mitochondrial dysfunction leading to retinal ganglion cell (RGC) death and ultimately loss of vision. They are, therefore, excellent models with which to investigate this ubiquitous disease process-implicated in both common polygenetic ocular diseases (e.g., Glaucoma) and late-onset central nervous system neurodegenerative diseases (e.g., Parkinson disease). In recent years, cellular and animal models of LHON and DOA have matured in parallel with techniques (such as RNA-seq) to determine and analyze the transcriptomes of affected cells. This confluence leaves us at a particularly exciting time with the potential for the identification of novel pathogenic players and therapeutic targets. Here, we present a discussion of the importance of inherited optic neuropathies and how transcriptomic techniques can be exploited in the development of novel mutation-independent, neuroprotective therapies

Prevalence of neurogenetic disorders in the North of England.

OBJECTIVE: Genetic disorders enter the differential diagnosis of common neurologic diseases, but their overall prevalence is not known. We set out to determine their minimum prevalence. METHODS: Meta-analysis of epidemiologic data gathered from the same geographic region in the North of England. RESULTS: Monogenic neurologic disorders affect at least 90.9/100,000 (95% confidence interval 87.6-94.3), or 1 in 1,100 of the population in Northern England. CONCLUSION: As a group, neurogenetic disorders are not rare. These findings have implications for clinical service delivery

From Transcriptomics to Treatment in Inherited Optic Neuropathies.

Inherited optic neuropathies, including Leber Hereditary Optic Neuropathy (LHON) and Dominant Optic Atrophy (DOA), are monogenetic diseases with a final common pathway of mitochondrial dysfunction leading to retinal ganglion cell (RGC) death and ultimately loss of vision. They are, therefore, excellent models with which to investigate this ubiquitous disease process-implicated in both common polygenetic ocular diseases (e.g., Glaucoma) and late-onset central nervous system neurodegenerative diseases (e.g., Parkinson disease). In recent years, cellular and animal models of LHON and DOA have matured in parallel with techniques (such as RNA-seq) to determine and analyze the transcriptomes of affected cells. This confluence leaves us at a particularly exciting time with the potential for the identification of novel pathogenic players and therapeutic targets. Here, we present a discussion of the importance of inherited optic neuropathies and how transcriptomic techniques can be exploited in the development of novel mutation-independent, neuroprotective therapies