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Angiogenesis gene therapy to rescue ischaemic tissues: achievements and future directions.

ABSTRACT: Ischaemic diseases are characterized by an impaired supply of blood resulting from narrowed or blocked arteries that starve tissues of needed nutrients and oxygen. Coronary-atherosclerosis induced myocardial infarction is one of the leading causes of mortality in developed countries. Ischaemic disease also affects the lower extremities. Considerable advances in both surgical bypassing and percutaneous revascularization techniques have been reached. However, many patients cannot benefit from these therapies because of the extension of arterial occlusion and/or microcirculation impairment. Consequently, the need for alternative therapeutic strategies is compelling. An innovative approach consists of stimulating collateral vessel growth, a natural host defence response that intervenes upon occurrence of critical reduction in tissue perfusion (Isner & Asahara, 1999). This review will debate the relevance of therapeutic angiogenesis for promotion of tissue repair. The following issues will receive attention: (a) vascular growth patterns, (b) delivery systems for angiogenesis gene transfer, (c) achievements of therapeutic angiogenesis in myocardial and peripheral ischaemia, and (d) future directions to improve effectiveness and safety of vascular gene therapy.

SUBMITTER: Emanueli C

PROVIDER: S-EPMC1572862 | biostudies-other | 2001 Aug

REPOSITORIES: biostudies-other

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Project description:BackgroundLeber congenital amaurosis (LCA) is a congenital retinal dystrophy that results in significant and often severe vision loss at an early age. Comprehensive analysis of the genetic mutations and phenotypic correlations in LCA patients has allowed for significant improvements in understanding molecular pathways of photoreceptor degeneration and dysfunction. The purpose of this article is to review the literature on the subject of retinal gene therapy for LCA, including historical descriptions, preclinical animal studies, and human clinical trials.MethodsA literature search of peer-reviewed and indexed publications from 1996-2011 using the PubMed search engine was performed. Key terms included "Leber congenital amaurosis", LCA, RPE65, "cone-rod dystrophy", "gene therapy", and "human trials" in various combinations. Seminal articles prior to 1996 were selected from primary sources and reviews from the initial search. Articles were chosen based on pertinence to clinical, genetic, and therapeutic topics reviewed in this manuscript. Fundus photographs from LCA patients were obtained retrospectively from the clinical practice of one of the authors (R.A.S).ResultsHerein, we reviewed the literature on LCA as a genetic disease, the results of human gene therapy trials to date, and possible future directions towards treating inherited retinal diseases at the genetic level. Original descriptions of LCA by Theodor Leber and subsequent research demonstrate the severity of this disease with early-onset blindness. Discoveries of the causative heritable mutations revealed genes and protein products involved in photoreceptor development and visual transduction. Animal models have provided a means to test novel therapeutic strategies, namely gene therapy. Stemming from these experiments, three independent clinical trials tested the safety of subretinal delivery of viral gene therapy to patients with mutations in the RPE65 gene. More recently, efficacy studies have been conducted with encouraging results.ConclusionsInitial safety studies indicated promising results of subretinal delivery of viral vector with subclinical immunologic or surgical sequelae. Overall, these initial studies demonstrate that viral vector gene therapy results are very promising, safe, and effective. Future studies measuring potential improvement in photoreceptor function may rely on recent advances in retinal imaging and electrophysiologic testing.

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Angiogenesis gene therapy to rescue ischaemic tissues: achievements and future directions.

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