Suppression of ocular neovascularization with siRNA targeting VEGF receptor 1 (original) (raw)
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Gene therapy for ocular angiogenesis
Clinical Science, 2003
Ocular neovascularization is a central feature of diabetic retinopathy and age-related macular degeneration. These conditions are the major causes of blindness in the developed world. Current treatments are of limited efficacy and associated with significant adverse effects. Characterization of the molecular and cellular events involved in angiogenesis has led to the identification of a number of angiostatic molecules with potential therapeutic value. The systemic administration of small molecule angiostatic proteins risks significant systemic adverse effects and the effect of their intraocular injection is short-lived. Local gene transfer, however, offers the possibility of targeted, sustained and regulatable delivery of angiostatic proteins to the retina after a single procedure to introduce a vector to an intraocular site. The effect of intra-ocular delivery of recombinant viruses carrying genes encoding angiostatic proteins has been demonstrated in rodent models of ocular neovas...
Gene therapy progress and prospects: the eye
Gene Therapy, 2006
The eye has unique advantages as a target organ for gene therapy of both inherited and acquired ocular disorders and offers a valuable model system for gene therapy. The eye is readily accessible to phenotypic examination and investigation of therapeutic effects in vivo by fundus imaging and electrophysiological techniques. Considerable progress has been made in the development of gene replacement therapies for retinal degenerations resulting from gene defects in photoreceptor cells (rds, RPGRIP, RS-1) and in retinal pigment epithelial cells (MerTK, RPE65, OA1) using recombinant adeno-associated virus and lentivirus-based vectors. Gene therapy also offers a potentially powerful approach to the treatment of complex acquired disorders such as those involving angiogenesis, inflammation and degeneration, by the targeted sustained intraocular delivery of therapeutic proteins. Proposals for clinical trials of gene therapy for early-onset retinal degeneration owing to defects in the gene encoding the visual cycle protein RPE65 have recently received ethical approval.
Recent advances in ocular gene therapy
Current Opinion in Ophthalmology, 2009
Recent breakthroughs: human gene therapy clinical trials-Leber's congenital amaurosis One of the most severe forms of inherited blindness in children is a group of diseases known as Leber's congenital amaurosis (LCA). LCA is a recessively inherited infantileonset rod-cone dystrophy that presents at birth with vision loss, nystagmus, and flat electroretinographic responses. It is caused by defects in a variety of single-gene defects that disrupt proteins implicated in various cellular functions, including ciliary transport, vitamin A metabolism, photoreceptor development, phagocytosis, and phototransduction (see Retnet, http://www.sph.uth.tmc.edu/RetNet). Defects in one gene, retinal pigment epithelium-specific protein 65 kDa (RPE65), cause one form of LCA, type LCA2, characterized by moderate vision impairment at
State-of-the-art gene-based therapies: the road ahead
Nature Reviews Genetics, 2011
The idea of gene-based therapeutics has been around for some time, but it only received serious attention with the advent of recombinant DNA technology and the ability to transfer and express exogenous genes in mammalian cells. The first clinical trials were carried out in the late 1980s, and at that stage it was predicted that gene therapy would become a treatment for serious diseases in just a matter of years. However, during the ensuing two decades, numerous obstacles have tempered the enthusiasm for gene therapy. More recently, some important technical barriers have been overcome to the point where successful examples exist of treating specific diseases, as well as encouraging new preclinical trials that will expand on the number of treatable disease-targets. This Review provides insights into the state-of-theart accomplishments made with gene-based therapies and the major barriers that need to be overcome before they are more widely implemented by the medical community. The Review starts by describing the general approaches used-highlighting the growing application of therapies involving the transcription of non-coding RNA-and some of the practical considerations that are common to all gene transfer studies. The most clinically relevant vectors are discussed, providing examples of current successes (such as higher gene transfer efficiency and lower immunological responses) and the areas in which more effort is required to overcome technical barriers. The reader is referred to three other Reviews in this Focus issue that cover the use of viral vectors 1 , silencing-based therapies 2 and cell-based therapies 3 in greater detail. I end with some thoughts on the prospects for the future applications of gene therapy in the era of personalized genomic medicine. Although gene therapy has had a rocky coursewhich has been exacerbated in part owing to scepticism from some parts of the scientific community-it is now emerging as a promising discipline as a result of technical advances and the successful treatment of several devastating medical conditions. The goals of gene therapy Gene-based therapeutics is broadly defined as the introduction, using a vector, of nucleic acids into cells with the intention of altering gene expression to prevent, halt or reverse a pathological process. Here, I restrict the definition to include exogenous nucleic acids that provide a transcriptional template for the expression of a protein-coding or non-coding nucleic acid. Gene therapy can be carried out by three routes-gene addition, gene correction/alteration and gene knockdown-that are sometimes used in combination. The vectors can be administered in vivo or ex vivo using autologous cells derived from an individual patient. Depending on the vector, the therapeutic DNA either integrates into host chromosomal DNA or exists as an episomal vector. Gene addition and correction. Of the approaches mentioned above, gene addition is the most commonly attempted in current preclinical and clinical studies; it is used to provide therapeutic benefit or to supply a protein that is missing owing to genetic mutation. The least common of the techniques, gene correction/ alteration, has gained a lot of attention and has been covered in a recent Review 4 : in this approach, zinc finger nucleases and DNA recombination technologies are used to alter genomic sequences to correct a
Proceedings of the National Academy of Sciences, 1997
In recent years, there have been a number of technological breakthroughs that have allowed for clinical trials in gene therapy to be initiated. In combination with the genome initiative, the potential for new therapeutics is limitless. Although an enormous amount of information has been obtained in a relatively short period of time, gene therapy is not yet ready for wide-scale practice. Some of the successes and obstacles that remain are summarized in this report.
12th Annual Congress of the European Society of Gene Therapy
Expert Opinion on Biological Therapy, 2005
The 2004 European Society of Gene Therapy (ESGT) meeting took place at Tampere Hall in Finland and highlighted advances in a variety of topics, including cancer, zinc-fingers, stem cells, small interfering RNA (siRNA), microRNA, and recent developments of non-viral and viral vectors. This meeting was attended by 513 participants from 32 countries, and included 106 oral and 224 poster presentations. One of the aims of this meeting was to take a critical look at gene therapy and the prospects for the future. Several presentations reported on RNA-based technologies, such as siRNA, as potential new classes of therapeutics against a wide range of diseases and for use in expression libraries to identify functional genes involved in biological phenotypes. Critical assessments were made of other aspects of gene therapy, such as genome editing and the use of protein transduction domains (PTDs) in gene-and protein-based therapies, where many researchers have failed to reproduce initial findings reported in the literature. Safety issues related to viral vectors were also important areas of discussion, especially following details released by the UK Gene Therapy Advisory Committee of perhaps the first known case of lentiviral vector-associated oncogenesis. Finally, updates were presented on the clinical development of viral vectors in anticancer therapies with evidence of significant improvements in the mean survival of patients.
Gene therapy for angiogenesis, restenosis and related diseases
Experimental Gerontology, 1999
Gene therapy may be useful for the treatment of atherosclerosis and related diseases. Gene transfer to vascular system can be performed both via intravascular and extravascular routes. Gene transfer to other tissues, such as liver and muscle, can also be used. The first clinical trials for the induction of therapeutic angiogenesis with VEGF gene transfer are under way, and preliminary results are promising. In the prevention of restenosis genes inhibiting cellular proliferation and increasing NO production, such as NOS and VEGF, have been used. However, more basic research is needed to fully understand pathophysiological mechanisms involved in conditions related to atherosclerosis. Also, further developments in gene transfer vectors and gene delivery techniques are required for the improvement of the efficacy of gene therapy.
Ocular Gene Therapy: A Literature Review With Focus on Current Clinical Trials
Cureus
Gene therapy has been one of the most researched topics in the last decade. It has now become a revolutionized therapeutic tool of modern medicine. Gene therapy is the alteration of the defective gene involved in the disease process in the host cells. It delivers therapeutic genetic information via modified viral or non-viral vectors. Ocular gene therapy, in particular, has progressed in treating inherited retinal diseases since the eye is a favourable organ for gene therapy development. The advantage of the eye as a target for gene therapy is attributed to its easy accessibility and blood-ocular barrier. Several ongoing clinical trials are investigating various gene therapies for other ocular diseases, including neovascular agerelated macular degeneration, retinitis pigmentosa (RP), Usher syndrome, glaucoma, and several others. However, there are challenges such as ocular inflammation and humoral response, infection by the viral vectors, and insertional mutagenesis. These limitations depend on several factors; whether viral or non-viral vectors are used, which viral vectors were used, the route of administration, whether subretinal, intravitreal, or suprachoroidal, and the dose of vectors and the target tissue. These complications may lead to therapeutic failure and vision loss due to intraocular inflammation. This review aims to summarize existing knowledge about ocular gene therapy and the associated limitations we face, with a special focus on a few ongoing clinical trials.