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Vy Luong

Bio: Vy Luong is an academic researcher from University College London. The author has contributed to research in topics: Retinal & Retina. The author has an hindex of 16, co-authored 26 publications receiving 2003 citations. Previous affiliations of Vy Luong include UCL Institute of Ophthalmology & Visual Sciences.

Papers
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Journal ArticleDOI
TL;DR: In dogs, RPE65 gene therapy with the same vector at lower doses improved vision-guided behavior, but only higher doses resulted in improvements in retinal function that were detectable with the use of ERG, and comparison with the results obtained in the dog model indicates that there is a species difference in the amount of R PE65 required to drive the visual cycle.
Abstract: BackgroundMutations in RPE65 cause Leber’s congenital amaurosis, a progressive retinal degenerative disease that severely impairs sight in children. Gene therapy can result in modest improvements in night vision, but knowledge of its efficacy in humans is limited. MethodsWe performed a phase 1–2 open-label trial involving 12 participants to evaluate the safety and efficacy of gene therapy with a recombinant adeno-associated virus 2/2 (rAAV2/2) vector carrying the RPE65 complementary DNA, and measured visual function over the course of 3 years. Four participants were administered a lower dose of the vector, and 8 were administered a higher dose. In a parallel study in dogs, we investigated the relationship among vector dose, visual function, and electroretinography (ERG) findings. ResultsImprovements in retinal sensitivity were evident, to varying extents, in six participants for up to 3 years, peaking at 6 to 12 months after treatment and then declining. No associated improvement in retinal function was d...

599 citations

Journal ArticleDOI
TL;DR: It is shown that Aβ colocalizes with apoptotic retinal ganglion cells (RGC) in experimental glaucoma and induces significant RGC apoptosis in vivo in a dose- and time-dependent manner, and the combination of agents affecting multiple stages in the Aβ pathway may be the most effective strategy in Aβ-related diseases.
Abstract: The development of the devastating neurodegenerative condition, Alzheimer's disease, is strongly associated with amyloid-beta (Abeta) deposition, neuronal apoptosis, and cell loss. Here, we provide evidence that implicates these same mechanisms in the retinal disease glaucoma, a major cause of irreversible blindness worldwide, previously associated simply with the effects of intraocular pressure. We show that Abeta colocalizes with apoptotic retinal ganglion cells (RGC) in experimental glaucoma and induces significant RGC apoptosis in vivo in a dose- and time-dependent manner. We demonstrate that targeting different components of the Abeta formation and aggregation pathway can effectively reduce glaucomatous RGC apoptosis in vivo, and finally, that combining treatments (triple therapy) is more effective than monotherapy. Our work suggests that targeting the Abeta pathway provides a therapeutic avenue in glaucoma management. Furthermore, our work demonstrates that the combination of agents affecting multiple stages in the Abeta pathway may be the most effective strategy in Abeta-related diseases.

344 citations

Journal ArticleDOI
TL;DR: A noninvasive real-time imaging technique using confocal laser-scanning ophthalmoscopy to visualize single nerve cell apoptosis in vivo, which allows longitudinal study of disease processes that has not previously been possible.
Abstract: Apoptotic nerve cell death is implicated in the pathogenesis of several devastating neurodegenerative conditions, including glaucoma and Alzheimer's and Parkinson's diseases. We have devised a noninvasive real-time imaging technique using confocal laser-scanning ophthalmoscopy to visualize single nerve cell apoptosis in vivo, which allows longitudinal study of disease processes that has not previously been possible. Our method utilizes the unique optical properties of the eye, which allow direct microscopic observation of nerve cells in the retina. We have been able to image changes occurring in nerve cell apoptosis over hours, days, and months and show that effects depend on the magnitude of the initial apoptotic inducer in several models of neurodegenerative disease in rat and primate. This technology enables the direct observation of single nerve cell apoptosis in experimental neurodegeneration, providing the opportunity for detailed investigation of fundamental disease mechanisms and the evaluation of interventions with potential clinical applications, together with the possibility of taking this method through to patients.

273 citations

Journal ArticleDOI
TL;DR: The findings suggest that the lack of Ccl2 leads to a monocyte/macrophage-trafficking defect during aging and to an impaired recruitment of these cells to sites of laser injury.
Abstract: PURPOSE. Drusen, which are defined clinically as yellowish white spots in the outer retina, are cardinal features of age-related macular degeneration (AMD). Ccl2-knockout (Ccl2(-/-)) mice have been reported to develop drusen and phenotypic features similar to AMD, including an increased susceptibility to choroidal neovascularization (CNV). This study was conducted to investigate the nature of the drusenlike lesions in vivo and further evaluate the Ccl2(-/-) mouse as a model of AMD.METHODS. The eyes of 2- to 25-month-old Ccl2(-/-) and C57Bl/6 mice were examined in vivo by autofluorescence scanning laser ophthalmoscopy (AF-SLO) and electroretinography, and the extent of laser-induced CNV was measured by fluorescein fundus angiography. The retinal morphology was also assessed by immunohistochemistry and quantitative histologic and ultrastructural morphometry.RESULTS. The drusenlike lesions of Ccl2(-/-) mice comprised accelerated accumulation of swollen CD68(+), F4/80(+) macrophages in the subretinal space that were apparent as autofluorescent foci on AF-SLO. These macrophages contained pigment granules and phagosomes with outer segment and lipofuscin inclusions that may account for their autofluorescence. Only age-related retinal pigment epithelium (RPE) damage, photoreceptor loss, and sub-RPE deposits were observed but, despite the accelerated accumulation of macrophages, we identified no spontaneous development of CNV in the senescent mice and found a reduced susceptibility to laser-induced CNV in the Ccl2(-/-) mice.CONCLUSIONS. These findings suggest that the lack of Ccl2 leads to a monocyte/macrophage-trafficking defect during aging and to an impaired recruitment of these cells to sites of laser injury. Other, previously described features of Ccl2(-/-) mice that are similar to AMD may be the result of aging alone. (Invest Ophthalmol Vis Sci. 2009;50:5934-5943) DOI:10.1167/iovs.09-3462

200 citations

Journal ArticleDOI
TL;DR: This novel SSP model was validated as a useful tool for screening neuroprotective strategies in vivo and Combination therapy optimized to limit neurotoxic effects of MK801 may be an effective neuroProtective approach in retinal degenerative disease.
Abstract: Glaucoma is a major cause of worldwide irreversible blindness. Vision loss is attributed to retinal ganglion cell (RGC) death—a hallmark of glaucoma. Glaucomatous RGC death has been shown to involve the apoptosis pathway,1,2 and RGC apoptosis is one of the earliest signs of the disease process in glaucoma.1,3 Excessive activation of glutamate receptors from the release of glutamate from injured RGCs is heavily implicated in this process.4 Glutamate is the principal excitatory neurotransmitter in the central nervous system (CNS) and the retina and has been found to be increased in glaucoma.4-6 Inhibition or blockade of glutamate activity by modulation of its receptors—in particular, modulating NMDA (N-methyl-d-aspartate)-type glutamate receptors— has been advocated as an important strategy for neuroprotection in glaucoma. In the CNS and the retina, glutamate mediates excitatory neurotransmission via ion channel-associated (ionotropic) and G protein-coupled (metabotropic) receptors.7,8 The ionotropic (iGlu) receptors include NMDA, AMPA (α-animo-3-hydroxy-5-methyl-4-isoxazolepropionate), and KA (kainate) subtypes.7,8 A variety of NMDA antagonists, including memantine, MK801 (dizocilpine), dextromethorphan, flupirtine, and eliprodil, have been shown to ameliorate ischemia-induced insults to the retina. in vivo9-12 and in vitro,9,13 and to prevent or delay RGC death in several different models.9-11 NMDA receptors are thought to be heteromeric ion channel complexes that consist of two NR1 subunits and two NR2 subunits that can be either of the NR2A, -2B, -2C, or -2D type. In the rat retina, RGCs express both NR2A and -2B subunits, and it is thought that cells have a combination of different NMDA receptor types.14 Glutamate release has been implicated as a mechanism of RGC death in glaucoma,4,15-18 particularly with regard to secondary RGC degeneration.19-22 In addition, it has been heavily implicated in IOP-induced ischemia.23 It is very much the basis of several experimental glaucoma treatment studies, including those involving the NMDA antagonists MK801 in a rat ocular hypertensive model24 and memantine in rat and primate models,25-27 in which NMDA antagonists were shown to be neuroprotective. However, all these studies have relied on the quantification of RGC loss histologically and have not looked at the effects of agents on levels of RGC apoptosis. G protein-coupled glutamate receptors are called metabotropic (mGlu) receptors because they couple to intracellular second messengers.28,29 Eight mGlu receptor subtypes have been identified so far, and these have been classified into three groups.28,29 The mGluR1 and mGluR5 are coupled positively to phospholipase C, and both are included in group I, whereas the others are coupled negatively to adenylate cyclase and belong to group II (mGluR2 and mGluR3) and group III (mGluR4, mGluR6, mGluR7, and mGluR8).28,29 mGluRs can modulate excitatory and inhibitory synaptic transmission through various transduction pathways. There is evidence that activation of group I mGluRs increases neuronal excitation, whereas that of group II and III mGluRs reduces synaptic transmission29; therefore, group I mGluR antagonists and group II and III mGluR agonists can be thought to be neuroprotective.29 Various studies have shown expression of mRNA and/or receptor proteins for all mGluRs in the retina.30-34 Furthermore, it has been recently shown that expression of some mGluRs is stimulated in ocular hypertension (OHT) rodent glaucoma models,35 although the effects of a combination of group I mGluR antagonists and group II and III mGluR agonists were not found to be protective of RGC death in an axotomy and NMDA excitotoxic model.36 Although group II mGluR agonists by themselves have been reported to be neuroprotective against apoptotic neuronal death,29 until now, specific and targeted modulation of group II mGluRs has not been assessed in retinal apoptosis or glaucoma models. In this study, we sought to assess the effects of the broad-spectrum NMDA antagonist MK801 in our recently described model of staurosporine (SSP)-induced RGC apoptosis.3 To assess the relative contributions of NR2B-containing NMDA receptors in this apoptotic process, we also studied the effects of the NR2B-selective antagonist ifenprodil. As activation of group II mGluRs is neuroprotective through a different mechanism than that of NMDA antagonism, using this same model we investigated the actions of the group II agonist LY354740, and compared these effects with blockade of NMDA receptors. Finally, we assessed the effects of these agents in the OHT model of rodent glaucoma. All agents were investigated with our novel technique of in vivo RGC apoptosis imaging, which involves the correlation of the level of histologically confirmed RGC apoptosis to the effectiveness of neuroprotection.3

167 citations


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Journal ArticleDOI
15 Oct 2015-Nature
TL;DR: Technology for editing genes and correcting inherited mutations, the engagement of stem cells to regenerate tissues and the effective exploitation of powerful immune responses to fight cancer are also contributing to the revitalization of gene therapy.
Abstract: Recent clinical trials of gene therapy have shown remarkable therapeutic benefits and an excellent safety record. They provide evidence for the long-sought promise of gene therapy to deliver 'cures' for some otherwise terminal or severely disabling conditions. Behind these advances lie improved vector designs that enable the safe delivery of therapeutic genes to specific cells. Technologies for editing genes and correcting inherited mutations, the engagement of stem cells to regenerate tissues and the effective exploitation of powerful immune responses to fight cancer are also contributing to the revitalization of gene therapy.

918 citations

Journal ArticleDOI
12 Jan 2018-Science
TL;DR: The pioneering work that led the gene therapy field to its current state is reviewed, gene-editing technologies that are expected to play a major role in the field's future are described, and practical challenges in getting these therapies to patients who need them are discussed.
Abstract: BACKGROUND Nearly five decades ago, visionary scientists hypothesized that genetic modification by exogenous DNA might be an effective treatment for inherited human diseases. This “gene therapy” strategy offered the theoretical advantage that a durable and possibly curative clinical benefit would be achieved by a single treatment. Although the journey from concept to clinical application has been long and tortuous, gene therapy is now bringing new treatment options to multiple fields of medicine. We review critical discoveries leading to the development of successful gene therapies, focusing on direct in vivo administration of viral vectors, adoptive transfer of genetically engineered T cells or hematopoietic stem cells, and emerging genome editing technologies. ADVANCES The development of gene delivery vectors such as replication-defective retro viruses and adeno-associated virus (AAV), coupled with encouraging results in preclinical disease models, led to the initiation of clinical trials in the early 1990s. Unfortunately, these early trials exposed serious therapy-related toxicities, including inflammatory responses to the vectors and malignancies caused by vector-mediated insertional activation of proto-oncogenes. These setbacks fueled more basic research in virology, immunology, cell biology, model development, and target disease, which ultimately led to successful clinical translation of gene therapies in the 2000s. Lentiviral vectors improved efficiency of gene transfer to nondividing cells. In early-phase clinical trials, these safer and more efficient vectors were used for transduction of autologous hematopoietic stem cells, leading to clinical benefit in patients with immunodeficiencies, hemoglobinopathies, and metabolic and storage disorders. T cells engineered to express CD19-specific chimeric antigen receptors were shown to have potent antitumor activity in patients with lymphoid malignancies. In vivo delivery of therapeutic AAV vectors to the retina, liver, and nervous system resulted in clinical improvement in patients with congenital blindness, hemophilia B, and spinal muscular atrophy, respectively. In the United States, Food and Drug Administration (FDA) approvals of the first gene therapy products occurred in 2017, including chimeric antigen receptor (CAR)–T cells to treat B cell malignancies and AAV vectors for in vivo treatment of congenital blindness. Promising clinical trial results in neuromuscular diseases and hemophilia will likely result in additional approvals in the near future. In recent years, genome editing technologies have been developed that are based on engineered or bacterial nucleases. In contrast to viral vectors, which can mediate only gene addition, genome editing approaches offer a precise scalpel for gene addition, gene ablation, and gene “correction.” Genome editing can be performed on cells ex vivo or the editing machinery can be delivered in vivo to effect in situ genome editing. Translation of these technologies to patient care is in its infancy in comparison to viral gene addition therapies, but multiple clinical genome editing trials are expected to open over the next decade. OUTLOOK Building on decades of scientific, clinical, and manufacturing advances, gene therapies have begun to improve the lives of patients with cancer and a variety of inherited genetic diseases. Partnerships with biotechnology and pharmaceutical companies with expertise in manufacturing and scale-up will be required for these therapies to have a broad impact on human disease. Many challenges remain, including understanding and preventing genotoxicity from integrating vectors or off-target genome editing, improving gene transfer or editing efficiency to levels necessary for treatment of many target diseases, preventing immune responses that limit in vivo administration of vectors or genome editing complexes, and overcoming manufacturing and regulatory hurdles. Importantly, a societal consensus must be reached on the ethics of germline genome editing in light of rapid scientific advances that have made this a real, rather than hypothetical, issue. Finally, payers and gene therapy clinicians and companies will need to work together to design and test new payment models to facilitate delivery of expensive but potentially curative therapies to patients in need. The ability of gene therapies to provide durable benefits to human health, exemplified by the scientific advances and clinical successes over the past several years, justifies continued optimism and increasing efforts toward making these therapies part of our standard treatment armamentarium for human disease.

843 citations

Journal ArticleDOI
TL;DR: Data is summarized that support examination of the eyes as a noninvasive approach to the diagnosis of select CNS diseases, and the use of the eye as a valuable model to study the CNS.
Abstract: Philosophers defined the eye as a window to the soul long before scientists addressed this cliche to determine its scientific basis and clinical relevance. Anatomically and developmentally, the retina is known as an extension of the CNS; it consists of retinal ganglion cells, the axons of which form the optic nerve, whose fibres are, in effect, CNS axons. The eye has unique physical structures and a local array of surface molecules and cytokines, and is host to specialized immune responses similar to those in the brain and spinal cord. Several well-defined neurodegenerative conditions that affect the brain and spinal cord have manifestations in the eye, and ocular symptoms often precede conventional diagnosis of such CNS disorders. Furthermore, various eye-specific pathologies share characteristics of other CNS pathologies. In this Review, we summarize data that support examination of the eye as a noninvasive approach to the diagnosis of select CNS diseases, and the use of the eye as a valuable model to study the CNS. Translation of eye research to CNS disease, and deciphering the role of immune cells in these two systems, could improve our understanding and, potentially, the treatment of neurodegenerative disorders.

829 citations

Journal ArticleDOI
TL;DR: This body of work has considerably updated and expanded the view of how RGCs might die in glaucoma and has revealed novel, potential targets for neuroprotection.

738 citations