Marcela Votruba

Marcela Votruba
Cardiff University | CU · School of Vision Sciences

MA BM BCh FRCOphth PhD FLSW
Investigating novel therapeutic interventions in OPA1 related autosomal dominant optic atrophy in a variety of models.

About

160
Publications
25,315
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Introduction
The Mitochondria and Vision Lab is interested in the role that mitochondria play in neurodegenerative diseases of the eye.
Additional affiliations
January 2014 - present
Cardiff University
Position
  • Head of Department
October 2012 - January 2014
Cardiff University
Position
  • Professor
March 2003 - October 2003
Moorfields Eye Hospital NHS Foundation Trust
Position
  • Consultant

Publications

Publications (160)
Article
Full-text available
Primary mitochondrial disorders encompass a wide range of clinical presentations and a spectrum of severity. They currently lack effective disease‐modifying therapies and have a high mortality and morbidity rate. It is therefore essential to know that competitively‐funded research designed by academics meets core needs of people with mitochondrial...
Article
Purpose Global spending on retinal biologic medicines is expected to reach $28M USD by 2025. The first biosimilars (BioSim) of anti-vascular endothelial growth factors (anti-VEGF) are expected to launch in Europe in 2022; cutting costs and improving access to treatment. Physician surveys show concerns over Biosimilars – due to abbreviated regulator...
Article
Purpose Recent increased understanding of molecular and genetic causes of many inherited eye diseases opens the way to novel therapeutic interventions. The key to drug discovery is in delivering precision targets for treatment that open a therapeutic index over toxicity. We set out to define what type of treatments are emerging, against what target...
Article
Full-text available
Retinal ganglion cells (RGCs) undergo dendritic pruning in a variety of neurodegenerative diseases, including glaucoma and autosomal dominant optic atrophy (ADOA). Axotomising RGCs by severing the optic nerve generates an acute model of RGC dendropathy, which can be utilized to assess the therapeutic potential of treatments for RGC degeneration. Ph...
Article
Mitochondrial optic neuropathies are a group of optic nerve atrophies exemplified by the two commonest conditions in this group, autosomal dominant optic atrophy (ADOA) and Leber’s hereditary optic neuropathy (LHON). Their clinical features comprise reduced visual acuity, colour vision deficits, centro-caecal scotomas and optic disc pallor with thi...
Article
Full-text available
Nicotinamide adenine dinucleotide (NAD) is a REDOX cofactor and metabolite essential for neuronal survival. Glaucoma is a common neurodegenerative disease in which neuronal levels of NAD decline. We assess the effects of nicotinamide (a precursor to NAD) on retinal ganglion cells (the affected neuron in glaucoma) in normal physiological conditions...
Article
Full-text available
This study investigates whether reduced optic atrophy 1 (Opa1) level promotes apoptosis and retinal vascular lesions associated with diabetic retinopathy (DR). Four groups of mice: wild type (WT) control mice, streptozotocin (STZ)-induced diabetic mice, Opa1+/− mice, and diabetic Opa1+/− mice were used in this study. 16 weeks after diabetes onset,...
Article
Full-text available
Autosomal Dominant Optic Atrophy (ADOA) is an ophthalmological condition associated primarily with mutations in the OPA1 gene. It has variable onset, sometimes juvenile, but in other patients, the disease does not manifest until adult middle age despite the presence of a pathological mutation. Thus, individuals carrying mutations are considered hea...
Article
Purpose The primary mitochondrial disorders encompass a wide‐reaching number of clinical presentations and a spectrum of severity. It is therefore vital to know that research that is designed by academics and competitively funded, meets the core needs of people with mitochondrial disorders and their clinicians. Methods The Priority Setting Partner...
Article
BACKGROUND Leber hereditary optic neuropathy (LHON) leads to bilateral central vision loss. In a clinical trial setting, idebenone has been shown to be safe and to provide a trend toward improved visual acuity, but long-term evidence of effectiveness in real-world clinical practice is sparse. METHODS Open-label, multicenter, retrospective, noncontr...
Article
Leber's hereditary optic neuropathy (LHON) is a rare genetic mitochondrial disease and the primary cause of chronic visual impairment for at least 1 in 10 000 individuals in the U.K. Treatment options remain limited, with only a few drug candidates and therapeutic approaches, either approved or in development. Recently, idebenone has been investiga...
Preprint
Full-text available
Nicotinamide adenine dinucleotide (NAD) is a REDOX cofactor and metabolite essential for neuronal survival. Glaucoma is a common neurodegenerative disease in which neuronal levels of NAD decline. Repleting NAD via dietary supplementation of nicotinamide (a precursor to NAD) is effective in preventing retinal ganglion cell neurodegeneration in mouse...
Article
Full-text available
Glaucoma and age-related macular degeneration are leading causes of irreversible blindness worldwide with significant health and societal burdens. To date, no clinical cures are available and treatments target only the manageable symptoms and risk factors (but do not remediate the underlying pathology of the disease). Both diseases are neurodegener...
Article
Full-text available
A healthy mitochondrial network is essential for the maintenance of neuronal synaptic integrity. Mitochondrial and metabolic dysfunction contributes to the pathogenesis of many neurodegenerative diseases including dementia. OPA1 is the master regulator of mitochondrial fusion and fission and is likely to play an important role during neurodegenerat...
Article
Full-text available
Mitochondria are known to play an essential role in photoreceptor function and survival that enables normal vision. Within photoreceptors, mitochondria are elongated and extend most of the inner-segment length, where they supply energy for protein synthesis and the phototransduction machinery in the outer segment, as well as acting as a calcium sto...
Article
Full-text available
Purpose: Retinal ganglion cells (RGCs) are susceptible to mitochondrial deficits and also the major cell type affected in patients with mutations in the OPA1 gene in autosomal dominant optic atrophy (ADOA). Here, we characterized mitochondria in RGCs in vitro from a heterozygous B6; C3-Opa1Q285STOP (Opa1+/-) mouse model to investigate mitochondria...
Article
Full-text available
Objective To improve the genetic diagnosis of dominant optic atrophy (DOA), the most frequently inherited optic nerve disease, and infer genotype-phenotype correlations. Methods Exonic sequences of 22 genes were screened by new-generation sequencing in patients with DOA who were investigated for ophthalmology, neurology, and brain MRI. Results We...
Article
Idebenone has recently been investigated as a drug therapy for Leber's hereditary optic neuropathy (LHON), a rare genetic mitochondrial disease that causes rapid and progressive bilateral vision loss. Although several studies have shown that idebenone can promote vision recovery in patients with LHON, the evidence for the efficacy of idebenone is s...
Article
Full-text available
Objective: Autosomal dominant optic atrophy (ADOA) starts in early childhood with loss of visual acuity and color vision deficits. OPA1 mutations are responsible for the majority of cases, but in a proportion of patients with a clinical diagnosis of ADOA, the cause remains unknown. This study aimed to identify novel ADOA-associated genes and explo...
Article
Full-text available
Purpose: To assess the topographic relationship between the photopic negative response (PhNR) and retinal ganglion cell distribution in healthy individuals. Method: Data was recorded from 16 healthy participants. The amplitude of PhNRs obtained in response to focal long duration (250 ms) and brief flash (5 ms), red (660 nm) on blue (469 nm) stim...
Article
Full-text available
Purpose In this prospective observational comparative case series, we aimed to study the peripapillary capillary network with spectral‐domain optical coherence tomography angiography (OCT‐A) in Leber hereditary optic neuropathy (LHON). Methods Twelve eyes of six individuals, of these three males (five eyes) after clinical onset of visual impairmen...
Article
Full-text available
Background: Autosomal dominant optic atrophy (ADOA) is usually caused by mutations in the essential gene, OPA1. This encodes a ubiquitous protein involved in mitochondrial dynamics, hence tissue specificity is not understood. Dysregulated mitophagy (mitochondria recycling) is implicated in ADOA, being increased in OPA1 patient fibroblasts. Furtherm...
Data
Mapping of the mRFP transgene. The insertion of the mRFP transgene was investigated by paired-end sequencing. The insert is located in the 3rd exon of the pkn1 gene, which has been confirmed by PCR using a common forward primer (green) and two different reverse primers; one (red) 1,500 bp from the forward primer in the wild type genome (blue) and o...
Data
Analysis of OPA1 expression in the MEFs used. Protein extracts were prepared from wt, RedMIT-GFP-LC3 and RedMIT-GFP-LC3-OPA1Q285STOP MEFs and analyzed on a 8% acrylamide gel. The OPA1 signal was detected using a rabbit anti-OPA1 antibody (abcam ab42364) and revealed using a polyclonal goat anti-rabbit secondary antibody (Dako P0448) coupled to an E...
Data
mRFP and GFP transgenes do not affect mice reproductive success.
Data
Images from sections of brain and spleen from control, RedMIT/GFP-LC3, and OPA1Q285STOP/RedMIT/GFP-LC3. Brain (Bottom) and spleen (Top) from non-fluorescent (control), RedMIT/GFP-LC3 and OPA1Q285STOP/RedMIT/GFP-LC3 mice were sectioned (10 μm) and imaged on a Zeiss LSM 700 inverted confocal microscope with a plan-Apo 63x NA 1.4 oil-immersion objecti...
Data
Movie of the RedMIT-GFP-LC3 MEFs. Live RedMIT-GFP-LC3 MEFs have been imaged using a custom Olympus IX81 inverted microscope equipped with temperature control (Solent scientific) every 30 s for 8 h. This can be used to quantify the early stages of mitophagy in real time.
Article
Full-text available
Alzheimer's disease (AD) is a neurodegenerative disease and the most common cause of senile dementia. It impairs the quality of life of a person and their family, posing a serious economic and social threat in developed countries. The fact that the diagnosis can only be definitively made post-mortem, or when the disease is fairly advanced, presents...
Article
Leber hereditary optic neuropathy (LHON) is currently estimated as the most frequent mitochondrial disease (1 in 27,000-45,000). Its molecular pathogenesis and natural history is now fairly well understood. LHON also is the first mitochondrial disease for which a treatment has been approved (idebenone-Raxone, Santhera Pharmaceuticals) by the Europe...
Article
Purpose With the context of the Ophthalmic Genetic Clinics, this presentation aims to explore the level of understanding of photoreceptor degeneration, the leading cause of inherited blindness, which presents with extreme genetic heterogeneity, making the molecular diagnosis a challenge. The promising future for inherited retinal dystrophies with t...
Article
Purpose Alzheimer's disease is a neurodegenerative disease and the most common cause of senile dementia. The fact that the diagnosis can only be definitively made postmortem, or when the disease is fairly advanced, presents a serious problem if novel therapeutic interventions are to be devised and used early in the course of the disease. Therefore...
Article
Purpose Mutations in OPA1 are the leading cause of dominant optic atrophy, a disease in which a progressive loss of retinal ganglion cells (RGCs) leads to blindness. In the B6;C3‐Opa1Q285STOP mouse, an Opa1 mutation causes a decrease in ATP production and a progressive loss in visual acuity, which coincides with pruning of the predominantly ON‐cent...
Data
Results of the macular and optic nerve head optical coherence tomography imaging.
Data
S-cone critical flicker fusion variables.
Data
L-cone critical flicker fusion variables.
Article
Full-text available
Leber inherited optic neuropathy (LHON) is characterized by subacute bilateral loss of central vision due to dysfunction and loss of retinal ganglion cells (RGCs). Comprehensive visual electrophysiological investigations (including pattern reversal visual evoked potentials, pattern electroretinography and the photopic negative response) performed o...
Article
Full-text available
Absorption of photon energy by neuronal mitochondria leads to numerous downstream neuroprotective effects. Red and near infrared (NIR) light are associated with significantly less safety concerns than light of shorter wavelengths and they are therefore, the optimal choice for irradiating the retina. Potent neuroprotective effects have been demonstr...
Article
Full-text available
Background The onset of Leber hereditary optic neuropathy (LHON) is relatively rare in childhood. This study describes the clinical and molecular genetic features observed in this specific LHON subgroup. Methods Our retrospective study consisted of a UK paediatric LHON cohort of 27 patients and 69 additional cases identified from a systematic revi...
Article
Full-text available
Purpose: Progressive retinal ganglion cell (RGC) loss is the pathological hallmark of autosomal dominant optic atrophy (DOA) caused by pathogenic OPA1 mutations. The aim of this study was to conduct an in-depth psychophysical study of the visual losses in DOA and to infer any selective vulnerability of visual pathways subserved by different RGC su...
Article
Full-text available
OBJECTIVE: To investigate mitophagy in 5 patients with severe dominantly inherited optic atrophy (DOA), caused by depletion of OPA1 (a protein that is essential for mitochondrial fusion), compared with healthy controls. METHODS: Patients with severe DOA (DOA plus) had peripheral neuropathy, cognitive regression, and epilepsy in addition to loss of...
Article
Objective: To investigate mitophagy in 5 patients with severe dominantly inherited optic atrophy (DOA), caused by depletion of OPA1 (a protein that is essential for mitochondrial fusion), compared with healthy controls. Methods: Patients with severe DOA (DOA plus) had peripheral neuropathy, cognitive regression, and epilepsy in addition to loss...
Article
Full-text available
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 comp...
Article
Full-text available
Purpose: To determine the molecular genetic cause in previously unreported probands with optic atrophy from the United Kingdom, Czech Republic and Canada. Methods: OPA1 coding regions and flanking intronic sequences were screened by direct sequencing in 82 probands referred with a diagnosis of bilateral optic atrophy. Detected rare variants were...
Article
Purpose To determine the molecular genetic cause in previously unreported probands with optic atrophy from the United Kingdom, Czech Republic and Canada. Methods OPA1 coding regions and flanking intronic sequences were screened by direct sequencing in 44 probands referred with a diagnosis of bilateral optic atrophy. Detected rare variants were ass...
Article
Primary inherited optic neuropathies are a group of blinding genetic disorders in which optic atrophy secondary to loss of retinal ganglion cells is a key clinical feature. The commonest causes world-wide are mutation in mitochondrial DNA (causing Leber's Hereditary Optic Neuropathy) and mutation in the nuclear gene, OPA1 (causing Autosomal Dominan...
Article
Full-text available
Mutations in the opa1 (optic atrophy 1) gene lead to autosomal dominant optic atrophy (ADOA), a hereditary eye disease. This gene encodes the Opa1 protein, a mitochondrial dynamin-related GTPase required for mitochondrial fusion and the maintenance of normal crista structure. The majority of opa1 mutations encode truncated forms of the protein, lac...
Article
Red light has been shown to provide neuroprotective effects. Axotomising the optic nerve initiates retinal ganglion cell (RGC) degeneration, and an early marker of this is dendritic pruning. We hypothesised that 670 nm light can delay axotomy induced dendritic pruning in the retinal explant. To test this hypothesis, we monitored the effects of 670...
Article
Full-text available
Mitochondrial dysfunction connects metabolic disturbance with numerous pathologies, but the significance of mitochondrial activity in bone remains unclear. We have, therefore, characterized the skeletal phenotype in the Opa3(L122P) mouse model for Costeff syndrome, in which a missense mutation of the mitochondrial membrane protein, Opa3, impairs mi...
Article
Full-text available
Dominant optic atrophy (DOA) arises from mutations in the OPA1 gene that promotes fusion of the inner mitochondrial membrane and plays a role in maintaining ATP levels. Patients display optic disc pallor, retinal ganglion cell (RGC) loss and bilaterally reduced vision. We report a randomized, placebo-controlled trial of idebenone at 2000 mg/kg/day...
Article
To explore the level of understanding and perceptions of inherited eye diseases and attitudes to genetic testing and gene therapy in a primary eye care setting.
Article
Purpose: To assess the effect of autosomal dominant optic atrophy (ADOA) on ON and OFF retinal ganglion cell (RGC) function by evaluating the ON and OFF components of the photopic negative response (PhNR). Methods: Twelve participants from six families with OPA1 ADOA and 16 age-matched controls were recruited. Electrophysiological assessment inv...
Conference Paper
Autosomal dominant optic atrophy (DOA) caused by OPA1 gene mutations leads to retinal ganglion cell (RGC) loss, but the pattern and chronology of loss remain poorly understood. Our aim was to characterise psychophysically the visual losses caused by DOA, and to infer any selective or progressive losses in the distinct visual pathways subserved by d...
Article
Background: Genetic eye pathology represents a significant percentage of the causes of blindness in industrialized countries. This study explores the level of understanding and perceptions of genetics and inherited eye diseases and the attitudes to genetic testing and gene therapy. Methods: The study was conducted in two parts. Participant group...
Conference Paper
Aim: The retinal origin of the N95 component of the PERG and the PhNR of the flash ERG is thought to be the retinal ganglion cells. If these components share a common retinal origin, then it may be expected that they would show a similar spatial distribution in the retina. This study aimed to investigate this by comparing the PERG and focal PhNR fr...
Article
Purpose To assess the affect of the missense mutation p.L122P in a mouse model of 3-methylglutaconic aciduria (MGA-III), a neuro-metabolic syndrome which presents with retinal and optic atrophy and neurological impairment.Methods Visual acuity was quantified in an optokinetic nystagmus drum by increasing the spatial frequency of the grating until a...
Article
Leber hereditary optic neuropathy and autosomal dominant optic atrophy are the two most common inherited optic neuropathies. The latter has been associated with mutations in the OPA1 and OPA3 genes. To date, only six families with OPA3-associated dominant optic atrophy have been reported. In order to identify additional families, we performed Sange...