12 research outputs found
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
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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
ADULT NEUROGENESIS AND DEPRESSION: AN INTRODUCTION
The following essay provides a summary of a seminar given on the sixth of November, 2010 at the combined annual congress,
held at Brussels of the Centro Studi Psichatrici Vrije Universiteit Brussel, Université Catholique de Louvain & the Bedfordshire
Centre for Mental Health Research. The talk aimed to present a brief taster, assuming no prior knowledge, of adult neurogenesis, the
formation of new nerve cells, in relation to the aetiology and treatment of depression.
The talk begins with an introduction to the principles of adult neurogenesis: from initial investigations by Ramon y Cajal in the
19th century, resulting in a "static brain hypothesis", to their subsequent challenge almost one hundred years later. The potential
functional implications emerging, especially in relation to depression, are explored. The fascinating effects of corticosteroids and
antidepressants are used as examples to explore the possible roles of neurogenesis that have led some to propose a neurogenic
theory of depression. Arguments against this theory are then presented. Finally, a consideration of future opinion: could
neurogenesis be less important in the aetiology of depression, but involved in its treatment - a property of antidepressant action
rather than a central final aetiological pathway.
In this young branch of neuroscience controversy abounds: our understanding of the process itself, its relations and most
importantly its implications are all in their infancy. This has allowed for some of the most interesting debate of recent years as to the
neurological basis and treatment of affective disorders
Comparing optogenetic approaches to visual restoration in a model of retinal degeneration
The inherited retinal degenerations (IRDs) are the most common cause of irreversible visual loss in the young - but therapeutic options have traditionally been limited. While genetically heterogeneous, the IRDs are linked by a final common pathway of visual loss secondary to photoreceptor death, with cells of the neural retina surviving relatively intact. The technique of optogenetics (inducing light sensitivity by exogenous expression of light sensitive proteins within cells) is developing as a therapeutic method to stimulate these surviving cells: returning light signals to the degenerate retina and ultimately restoring lost vision.
The aim of this thesis was to compare different optogenetic tools and cellular targets for optogenetic visual restoration in a model of inherited retinal degeneration in order to inform future translational work.
Three novel mouse models of retinal degeneration, additionally devoid of native melanopsin and incorporating cell specific Cre recombinase expression were devolved and validated to allow cell population specific targeting of genetic constructs both delivered transgenically and by using intravitreal injections of adenoassociated viral vectors (AAVs).
These models were used to isolate ON-bipolar cells from dissociated degenerate retina in the first comparison of gene expression profiles in such cells to their wildtype counterparts. This demonstrated a lack of changes likely to preclude these attractive cellular targets for therapeutic optogenetics.
Cell targeted delivery of a candidate optogenetic tool (melanopsin) using these models was compared to conventional (non-specific) AAV delivery. This showed restoration of retinal electrophysiological light responses on ex vivo multiple electrode array recordings with kinetics differing between delivery approaches. Targeted delivery of three candidate tools (melanopsin, rhodopsin and ReaChR- channelrhodopsin) were similarly compared with markedly differing response characteristics demonstrated between tools
Finally, translatable, compressed ON-bipolar cell specific promotors were used to produce a potentially translatable cell specific AAV delivery system. This was demonstrated to successfully deliver functional optogenetic tools to a degenerate retina in vivo.
Together, these data indicate that the described mouse lines form a useful model system with which to compare optogenetic vision restoration approaches. In addition, while no one optogenetic tool or target was demonstrated to be overall superior to another, the diversity of responses seen could in themselves represent a great opportunity to improve the quality of responses restored by this technique as it moves towards clinical translation for the treatment of inherited retinal degenerations
Chiasmal Misrouting in Infantile Nystagmus Syndrome (INS): Phenotypes in Patients With Molecular Diagnoses
Chiasmal misrouting, once believed to be pathognomonic for albinism, has been reported in cases of INS, independent of melanin pathway disruption. The purpose of this study is to test the hypothesis that there are clinical-electrophysiological parameters that correlate with particular genotypes in INS
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Inherited Optic Neuropathies: Real-World Experience in the Paediatric Neuro-Ophthalmology Clinic.
Peer reviewed: TruePublication status: PublishedFunder: Addenbrooke’s Charitable TrustFunder: National Eye Research Centre (UK)Funder: International Foundation for Optic Nerve Disease (IFOND)Funder: NIHR Biomedical Research Centre based at Moorfields Eye Hospital NHS Foundation Trust and the UCL Institute of OphthalmologyInherited optic neuropathies affect around 1 in 10,000 people in England; in these conditions, vision is lost as retinal ganglion cells lose function or die (usually due to pathological variants in genes concerned with mitochondrial function). Emerging gene therapies for these conditions have emphasised the importance of early and expedient molecular diagnoses, particularly in the paediatric population. Here, we report our real-world clinical experience of such a population, exploring which children presented with the condition, how they were investigated and the time taken for a molecular diagnosis to be reached. A retrospective case-note review of paediatric inherited optic neuropathy patients (0-16 years) in the tertiary neuro-ophthalmology service at Moorfields Eye Hospital between 2016 and 2020 identified 19 patients. Their mean age was 9.3 ± 4.6 (mean ± SD) years at presentation; 68% were male, and 32% were female; and 26% had comorbidities, with diversity of ethnicity. Most patients had undergone genetic testing (95% (n = 18)), of whom 43% (n = 8) received a molecular diagnosis. On average, this took 54.8 ± 19.5 weeks from presentation. A cerebral MRI was performed in 70% (n = 14) and blood testing in 75% (n = 15) of patients as part of their workup. Continual improvement in the investigative pathways for inherited optic neuropathies will be paramount as novel therapeutics become available
Retinal ganglion cell repopulation for vision restoration in optic neuropathy: a roadmap from the RReSTORe Consortium
Abstract Retinal ganglion cell (RGC) death in glaucoma and other optic neuropathies results in irreversible vision loss due to the mammalian central nervous system’s limited regenerative capacity. RGC repopulation is a promising therapeutic approach to reverse vision loss from optic neuropathies if the newly introduced neurons can reestablish functional retinal and thalamic circuits. In theory, RGCs might be repopulated through the transplantation of stem cell-derived neurons or via the induction of endogenous transdifferentiation. The RGC Repopulation, Stem Cell Transplantation, and Optic Nerve Regeneration (RReSTORe) Consortium was established to address the challenges associated with the therapeutic repair of the visual pathway in optic neuropathy. In 2022, the RReSTORe Consortium initiated ongoing international collaborative discussions to advance the RGC repopulation field and has identified five critical areas of focus: (1) RGC development and differentiation, (2) Transplantation methods and models, (3) RGC survival, maturation, and host interactions, (4) Inner retinal wiring, and (5) Eye-to-brain connectivity. Here, we discuss the most pertinent questions and challenges that exist on the path to clinical translation and suggest experimental directions to propel this work going forward. Using these five subtopic discussion groups (SDGs) as a framework, we suggest multidisciplinary approaches to restore the diseased visual pathway by leveraging groundbreaking insights from developmental neuroscience, stem cell biology, molecular biology, optical imaging, animal models of optic neuropathy, immunology & immunotolerance, neuropathology & neuroprotection, materials science & biomedical engineering, and regenerative neuroscience. While significant hurdles remain, the RReSTORe Consortium’s efforts provide a comprehensive roadmap for advancing the RGC repopulation field and hold potential for transformative progress in restoring vision in patients suffering from optic neuropathies