A comprehensive review of retinal gene therapy.
TL;DR: This review will provide a comprehensive summary of existing gene therapy clinical trials for several genetic forms of blindness and preclinical efficacy and safety studies in a variety of animal models of retinal disease which demonstrate strong potential for clinical application.
About: This article is published in Molecular Therapy.The article was published on 2013-03-01 and is currently open access. It has received 253 citations till now. The article focuses on the topics: C-Mer Tyrosine Kinase.
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TL;DR: In this article, the authors discuss current progress toward developing programmable nuclease-based therapies as well as future prospects and challenges, and discuss the potential to directly correct genetic mutations in affected tissues and cells to treat diseases that are refractory to traditional therapies.
Abstract: Recent advances in the development of genome editing technologies based on programmable nucleases have substantially improved our ability to make precise changes in the genomes of eukaryotic cells. Genome editing is already broadening our ability to elucidate the contribution of genetics to disease by facilitating the creation of more accurate cellular and animal models of pathological processes. A particularly tantalizing application of programmable nucleases is the potential to directly correct genetic mutations in affected tissues and cells to treat diseases that are refractory to traditional therapies. Here we discuss current progress toward developing programmable nuclease–based therapies as well as future prospects and challenges.
942 citations
01 Feb 2015
TL;DR: Current progress toward developing programmable nuclease–based therapies as well as future prospects and challenges are discussed.
Abstract: Recent advances in the development of genome editing technologies based on programmable nucleases have substantially improved our ability to make precise changes in the genomes of eukaryotic cells. Genome editing is already broadening our ability to elucidate the contribution of genetics to disease by facilitating the creation of more accurate cellular and animal models of pathological processes. A particularly tantalizing application of programmable nucleases is the potential to directly correct genetic mutations in affected tissues and cells to treat diseases that are refractory to traditional therapies. Here we discuss current progress toward developing programmable nuclease–based therapies as well as future prospects and challenges.
846 citations
TL;DR: This review describes how use-dependent blockers of the different isoforms could selectively block calcium channels in particular pathologies, such as nociceptive neurons in pain states or in epileptic brain circuits, and describes how selectivity for different subtypes of calcium channels may be achieved in the future.
Abstract: Voltage-gated calcium channels are required for many key functions in the body. In this review, the different subtypes of voltage-gated calcium channels are described and their physiologic roles and pharmacology are outlined. We describe the current uses of drugs interacting with the different calcium channel subtypes and subunits, as well as specific areas in which there is strong potential for future drug development. Current therapeutic agents include drugs targeting L-type Ca(V)1.2 calcium channels, particularly 1,4-dihydropyridines, which are widely used in the treatment of hypertension. T-type (Ca(V)3) channels are a target of ethosuximide, widely used in absence epilepsy. The auxiliary subunit α2δ-1 is the therapeutic target of the gabapentinoid drugs, which are of value in certain epilepsies and chronic neuropathic pain. The limited use of intrathecal ziconotide, a peptide blocker of N-type (Ca(V)2.2) calcium channels, as a treatment of intractable pain, gives an indication that these channels represent excellent drug targets for various pain conditions. We describe how selectivity for different subtypes of calcium channels (e.g., Ca(V)1.2 and Ca(V)1.3 L-type channels) may be achieved in the future by exploiting differences between channel isoforms in terms of sequence and biophysical properties, variation in splicing in different target tissues, and differences in the properties of the target tissues themselves in terms of membrane potential or firing frequency. Thus, use-dependent blockers of the different isoforms could selectively block calcium channels in particular pathologies, such as nociceptive neurons in pain states or in epileptic brain circuits. Of important future potential are selective Ca(V)1.3 blockers for neuropsychiatric diseases, neuroprotection in Parkinson's disease, and resistant hypertension. In addition, selective or nonselective T-type channel blockers are considered potential therapeutic targets in epilepsy, pain, obesity, sleep, and anxiety. Use-dependent N-type calcium channel blockers are likely to be of therapeutic use in chronic pain conditions. Thus, more selective calcium channel blockers hold promise for therapeutic intervention.
762 citations
Cites background from "A comprehensive review of retinal g..."
...…of channel protein in the cell membrane, as measured by imaging, gating charge determination, or various biochemical means (Josephson and Varadi, 1996; Kamp et al., 1996; Brice et al., 1997; Bichet et al., 2000; Altier et al., 2002; Cohen et al., 2005; Leroy et al., 2005; Cassidy et al., 2014)....
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TL;DR: In teleost fish, the response of Müller glia to retinal injury involves a reprogramming event that imparts retinal stem cell characteristics and enables them to produce a proliferating population of progenitors that can regenerate all major retinal cell types and restore vision.
Abstract: Muller glia in the fish retina respond to injury by reprogramming to a stem-cell-like state that enables them to regenerate all of the major retinal cell types. Goldman reviews our current understanding of the mechanisms that regulate this regenerative response and considers how this knowledge might be applied to improve repair in the mammalian retina.
468 citations
TL;DR: The basic biology of AAV is reviewed, the history of progress in AAV vector technology, and some of the clinical and research applications where AAV has shown success are reviewed.
Abstract: Adeno-associated virus (AAV) is a small, nonenveloped virus that was adapted 30 years ago for use as a gene transfer vehicle. It is capable of transducing a wide range of species and tissues in vivo with no evidence of toxicity, and it generates relatively mild innate and adaptive immune responses. We review the basic biology of AAV, the history of progress in AAV vector technology, and some of the clinical and research applications where AAV has shown success.
373 citations
References
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TL;DR: This work has identified endostatin, an angiogenesis inhibitor produced by hemangioendothelioma, a 20 kDa C-terminal fragment of collagen XVIII that specifically inhibits endothelial proliferation and potently inhibitsAngiogenesis and tumor growth.
4,613 citations
TL;DR: Cellular organelles in the exocytic and endocytic pathways have a distinctive spatial distribution and communicate through an elaborate system of vesiculo-tubular transport.
Abstract: Cellular organelles in the exocytic and endocytic pathways have a distinctive spatial distribution and communicate through an elaborate system of vesiculo-tubular transport. Rab proteins and their effectors coordinate consecutive stages of transport, such as vesicle formation, vesicle and organelle motility, and tethering of vesicles to their target compartment. These molecules are highly compartmentalized in organelle membranes, making them excellent candidates for determining transport specificity and organelle identity.
3,373 citations
TL;DR: This finding demonstrated that a nucleotide change in a mitochondrial DNA energy production gene can result in a neurological disease.
Abstract: Leber's hereditary optic neuropathy is a maternally inherited disease resulting in optic nerve degeneration and cardiac dysrhythmia. A mitochondrial DNA replacement mutation was identified that correlated with this disease in multiple families. This mutation converted a highly conserved arginine to a histidine at codon 340 in the NADH dehydrogenase subunit 4 gene and eliminated an Sfa NI site, thus providing a simple diagnostic test. This finding demonstrated that a nucleotide change in a mitochondrial DNA energy production gene can result in a neurological disease.
2,230 citations
TL;DR: This study investigated the safety of subretinal delivery of a recombinant adeno-associated virus (AAV) carrying RPE65 complementary DNA (cDNA) and found three patients with LCA2 had an acceptable local and systemic adverse-event profile after delivery of AAV2.hRPE65v2.
Abstract: S um m a r y Leber's congenital amaurosis (LCA) is a group of inherited blinding diseases with onset during childhood. One form of the disease, LCA2, is caused by mutations in the retinal pigment epithelium-specific 65-kDa protein gene (RPE65). We investiga t ed the safety of subretinal delivery of a recombinant adeno-associated virus (AAV) carry- ing RPE65 complementary DNA (cDNA) (ClinicalTrials.gov number, NCT00516477). Three patients with LCA2 had an acceptable local and systemic adverse-event pro- file after delivery of AAV2.hRPE65v2. Each patient had a modest improvement in measures of retinal function on subjective tests of visual acuity. In one patient, an asymptomatic macular hole developed, and although the occurrence was considered to be an adverse event, the patient had some return of retinal function. Although the follow-up was very short and normal vision was not achieved, this study pro- vides the basis for further gene therapy studies in patients with LCA.
2,066 citations
TL;DR: Three new visual acuity charts facilitate quantitative use ofVisual acuity test results by providing high-contrast lettering on washable white polystyrene on which to test right and left eyes.
2,065 citations