A5076908022- Retinal Development and Disorders
- CRISPR and Genetic Engineering
- Virus-based gene therapy research
- Mitochondrial Function and Pathology
- Photoreceptor and optogenetics research
- Cancer, Hypoxia, and Metabolism
- Retinal Diseases and Treatments
- RNA regulation and disease
- bioluminescence and chemiluminescence research
- Neuroscience and Neural Engineering
- RNA Interference and Gene Delivery
- Cellular transport and secretion
- Retinopathy of Prematurity Studies
- Neuroblastoma Research and Treatments
- Neuroscience and Neuropharmacology Research
- Glioma Diagnosis and Treatment
- ATP Synthase and ATPases Research
- Photosynthetic Processes and Mechanisms
- Cell death mechanisms and regulation
- Cancer Research and Treatments
- Endoplasmic Reticulum Stress and Disease
- Ocular Disorders and Treatments
- Ubiquitin and proteasome pathways
- Phagocytosis and Immune Regulation
- Calpain Protease Function and Regulation
Trinity College Dublin
2015-2025
University Hospitals Birmingham NHS Foundation Trust
2023
University of Manchester
2005
Cancer Research UK Manchester Institute
2003
For dominantly inherited disorders development of gene therapies, targeting the primary genetic lesion has been impeded by mutational heterogeneity. An example is rhodopsin-linked autosomal dominant retinitis pigmentosa with over 150 mutations in rhodopsin gene. Validation a mutation-independent suppression and replacement therapy for this disorder undertaken. The provides means correcting defect manner thereby circumventing diversity. Separate adeno-associated virus (AAV) vectors were used...
RP2 mutations cause a severe form of X-linked retinitis pigmentosa (XLRP). The mechanism RP2-associated retinal degeneration in humans is unclear, and animal models XLRP do not recapitulate this phenotype. Here, we developed gene-edited isogenic knockout (RP2 KO) induced pluripotent stem cells (iPSCs) patient-derived iPSC to produce 3D organoids as human disease model. Strikingly, the KO showed peak rod photoreceptor cell death at day 150 (D150) with subsequent thinning organoid outer...
Mutational heterogeneity represents one of the greatest barriers impeding progress toward clinic gene therapies for many dominantly inherited disorders. A general strategy suppression in conjunction with replacement has been proposed to overcome this mutational heterogeneity. In current study, various aspects are explored a dominant form retinal degeneration, retinitis pigmentosa (RP), caused by mutations rhodopsin (RHO-adRP). While > 200 have identified (RHO), principle, and may be employed...
Leber hereditary optic neuropathy (LHON) is a mitochondrially inherited form of visual dysfunction caused by mutations in several genes encoding subunits the mitochondrial respiratory NADH-ubiquinone oxidoreductase complex (complex I). Development gene therapies for LHON has been impeded genetic heterogeneity and need to deliver mitochondria retinal ganglion cells (RGCs), primarily affected LHON. The therapy under development entails intraocular injection nuclear yeast NADH-quinone (NDI1)...
The U4 small nuclear RNA (snRNA) forms a duplex with the U6 snRNA and, together U5 and ∼30 proteins, is part of U4/U6.U5 tri-snRNP complex, located at core major spliceosome. Recently, recurrent de novo variants in RNA, transcribed from RNU4-2 gene, least two other RNU genes were discovered to cause neurodevelopmental disorder. We detected inherited heterozygous (n.18_19insA n.56T>C) four out five RNU6 paralogues (n.55_56insG n.56_57insG) 135 individuals 62 families non-syndromic retinitis...
Mutations within the inosine 5′-monophosphate dehydrogenase 1 (IMPDH1) gene cause RP10 form of autosomal dominant retinitis pigmentosa (adRP), an early-onset retinopathy resulting in extensive visual handicap owing to progressive death photoreceptors. Apart from prevalence RP10, estimated account for 5–10% cases adRP United States and Europe, two observations render this RP attractive target therapy. First, we show that while recombinant adeno-associated viral (AAV)-mediated expression...
Recombinant adeno-associated virus (AAV) vectors are one of the main gene delivery vehicles used in retinal therapy approaches; however, there is a need to further improve efficacy, tropism, and safety these vectors. In this study, using CMV-EGFP expression cassette, we characterize utility AAV-PHP.eB, serotype recently developed by vivo directed evolution, which can cross blood-brain barrier target neurons with high efficacy mice. Systemic intravitreal AAV-PHP.eB resulted transduction...
The ability of AAV2/5 to target murine photoreceptors was used optimize vector expression cassettes for rhodopsin replacement gene therapy in the retina. Defects this pivotal protein visual cycle are associated with various forms inherited eye defects including retinitis pigmentosa. A final optimized design led functional correction and regeneration rod outer segment a mouse model deficiency. (RHO) encodes highly expressed G protein-coupled receptor that is central transduction...
The challenge of developing gene therapies for genetic forms blindness is heightened by the heterogeneity these conditions. However, mechanistic commonalities indicate key pathways that may be targeted in a gene-independent approach. Mitochondrial dysfunction and axon degeneration are common features many neurodegenerative conditions including retinal degenerations. Here we explore neuroprotective effect afforded absence sterile alpha Toll/interleukin-1 receptor motif-containing 1 (SARM1),...
Long-term memory is formed by alterations in glutamate-dependent excitatory synaptic transmission, which turn regulated synaptosomal protein of 25 kDa (SNAP-25), a key component the soluble N-ethylmaleimide-sensitive factor attachment receptor complex essential for exocytosis neurotransmitter-filled vesicles. Both reduced and excessive SNAP-25 activity has been implicated various disease states that involve cognitive dysfunctions such as attention deficit hyperactivity disorder,...
Recombinant adeno-associated virus (AAV) represents an efficient system for neuronal transduction. However, a potential drawback of AAV is its restricted packaging capacity approximately 5 kb. To bypass this limitation, number dual- and triple-vector strategies divide the transgene(s) between two or three AAVs. The success these approaches relies directly on cotransduction component Although proof concept stratagems has been demonstrated, underlying rate not analyzed quantitatively. In...
Significant advances in gene therapy have enabled exploration of therapies for inherited retinal disorders, many which are preclinical development or clinical evaluation. Gene conditions has led the way this growing field. The loss ganglion cells (RGCs) is a hallmark number disorders. As field matures innovations that aid refining and optimising efficacy demand. under RGC-related when delivered with recombinant adeno associated vectors (AAV), typically been expressed from ubiquitous promoter...
Abstract miRNA dysregulation is a hallmark of many neurodegenerative disorders, including those involving the retina. Up-regulation miR-1/133 and miR-142, down-regulation miR-183/96/182 has been described in RHO-P347S mouse retina, model for common form inherited blindness. High-throughput LC-MS/MS was employed to analyse protein expression predicted targets these miRNAs retinas; 133 potential target genes were identified. Pathway over-representation analysis suggests G-protein...
Glaucoma, a leading cause of blindness, is multifactorial condition that leads to progressive loss retinal ganglion cells (RGCs) and vision. Therapeutic interventions based on reducing ocular hypertension are not always successful. Emerging features glaucoma include mitochondrial dysfunction oxidative stress. In the current study, NDI1-based gene therapy, which improves function reduces reactive oxygen species, was delivered intraocularly via an adeno-associated viral vector (AAV). This...
As gene therapies for various forms of retinal degeneration progress toward human clinical trial, it will be essential to have a repertoire safe and efficient vectors delivery the target cells. Recombinant adeno-associated virus (AAV) serotype 2/2 has been shown well tolerated in retina provided efficacy patients some inherited degenerations. In this study, AAV2/8 AAV2/rh10 serotypes compared as means mammalian photoreceptor cells using specific promoter transgene expression. Both rescue...
Age-related macular degeneration (AMD) is the most common cause of blindness in aged population. However, to date there no effective treatment for dry form disease, representing 85–90% cases. AMD an immensely complex disease which affects, amongst others, both retinal pigment epithelium (RPE) and photoreceptor cells leads progressive loss central vision. Mitochondrial dysfunction RPE emerging as a key player disease. There are indications that during progression, first impaired turn...
AAV gene therapy for ocular disease has become a reality with the market authorisation of LuxturnaTM RPE65-linked inherited retinal degenerations and many therapies currently undergoing phase III clinical trials. Many disorders have mitochondrial involvement from primary such as Leber hereditary optic neuropathy (LHON), predominantly due to mutations in genes encoding subunits complex I, Mendelian multifactorial conditions dominant atrophy, glaucoma age-related macular degeneration. In this...