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      Gene Therapy for the Heart Lessons Learned and Future Perspectives

      1 , 2 , 1 , 3 , 2 , 1 , 2 , 3

      Circulation Research

      Ovid Technologies (Wolters Kluwer Health)

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          Abstract

          While clinical gene therapy celebrates its first successes, with several products already approved for clinical use and several hundreds in the final stages of the clinical approval pipeline, there is not a single gene therapy approach that has worked for the heart. Here, we review the past experience gained in the several cardiac gene therapy clinical trials that had the goal of inducing therapeutic angiogenesis in the ischemic heart and in the attempts at modulating cardiac function in heart failure. Critical assessment of the results so far achieved indicates that the efficiency of cardiac gene delivery remains a major hurdle preventing success but also that improvements need to be sought in establishing more reliable large animal models, choosing more effective therapeutic genes, better designing clinical trials, and more deeply understanding cardiac biology. We also emphasize a few areas of cardiac gene therapy development that hold great promise for the future. In particular, the transition from gene addition studies using protein-coding cDNAs to the modulation of gene expression using small RNA therapeutics and the improvement of precise gene editing now pave the way to applications such as cardiac regeneration after myocardial infarction and gene correction for inherited cardiomyopathies that were unapproachable until a decade ago.

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          Most cited references 3

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          Antisense oligonucleotides for the treatment of cardiomyopathy in Duchenne muscular dystrophy.

          Duchenne muscular dystrophy (DMD) is an X-linked recessive fatal neuromuscular disorder characterized by progressive muscle degeneration which affects one in 3500-5000 males born worldwide. DMD is caused by loss-of-function mutations in the dystrophin (DMD) gene encoding for dystrophin, a cytoskeletal protein that supports the structural integrity of myofibers during cycles of muscle contraction and relaxation. DMD patients do not only experience skeletal muscle deterioration but also severe cardiomyopathy, which is recognized as the current leading cause of death for the disease. Among the therapies being developed, exon skipping using antisense oligonucleotides (AOs) is one of the most promising approaches. AOs effectively restore dystrophin expression in skeletal muscles; however, they are highly inefficient in the heart due to endosomal entrapment. Improving skeletal muscle function without restoring dystrophin expression in cardiac tissue may exacerbate cardiomyopathy due to increased voluntary activity. This review consolidates the preclinical antisense approaches to improve dystrophin restoration, with a special focus on the heart.
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            The long noncoding RNA landscape in cardiovascular disease: a brief update

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              Fixing the genes.

               Jaroff L (1999)
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                Author and article information

                Contributors
                (View ORCID Profile)
                (View ORCID Profile)
                Journal
                Circulation Research
                Circ Res
                Ovid Technologies (Wolters Kluwer Health)
                0009-7330
                1524-4571
                May 08 2020
                May 08 2020
                : 126
                : 10
                : 1394-1414
                Affiliations
                [1 ]From the King’s College London, British Heart Foundation Centre of Research Excellence, School of Cardiovascular Medicine and Sciences, United Kingdom (A.C., H.A., M.G.)
                [2 ]Department of Medical, Surgical and Health Sciences, University of Trieste, Italy (A.C., G.S., M.G.)
                [3 ]Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy (H.A., M.G.).
                Article
                10.1161/CIRCRESAHA.120.315855
                © 2020

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