Cardiac Gene Therapy: From Concept to Reality

Kratlian, Razmig Garo; Hajjar, Roger J.

doi:10.1007/s11897-011-0077-1

Cited by 10 publications

(10 citation statements)

References 49 publications

(48 reference statements)

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“…most promising therapeutic options for heart failure. According to Kratlian and Hajjar, three main factors are necessary for successful gene therapy: (1) a molecular target appropriate for the disease, (2) successful vector design, and (3) targeted delivery methods (Kratlian and Hajjar, 2012). Here we describe a new molecular target, the X-linked inhibitor of apoptosis protein (XIAP), for cardiac gene therapy as well as optimization of the AAV capsid design for enhanced cardiac gene delivery.…”

Section: Discussionmentioning

confidence: 99%

X-Linked Inhibitor of Apoptosis Protein-Mediated Attenuation of Apoptosis, Using a Novel Cardiac-Enhanced Adeno-Associated Viral Vector

et al. 2012

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Successful amelioration of cardiac dysfunction and heart failure through gene therapy approaches will require a transgene effective at attenuating myocardial injury, and subsequent remodeling, using an efficient and safe delivery vehicle. Our laboratory has established a well-curated, high-quality repository of human myocardial tissues that we use as a discovery engine to identify putative therapeutic transgene targets, as well as to better understand the molecular basis of human heart failure. By using this rare resource we were able to examine ageand sex-matched left ventricular samples from (1) end-stage failing human hearts and (2) nonfailing human hearts and were able to identify the X-linked inhibitor of apoptosis protein (XIAP) as a novel target for treating cardiac dysfunction. We demonstrate that XIAP is diminished in failing human hearts, indicating that this potent inhibitor of apoptosis may be central in protecting the human heart from cellular injury culminating in heart failure. Efforts to ameliorate heart failure through delivery of XIAP compelled the design of a novel adenoassociated viral (AAV) vector, termed SASTG, that achieves highly efficient transduction in mouse heart and in cultured neonatal rat cardiomyocytes. Increased XIAP expression achieved with the SASTG vector inhibits caspase-3/7 activity in neonatal cardiomyocytes after induction of apoptosis through three common cardiac stresses: protein kinase C-c inhibition, hypoxia, or b-adrenergic receptor agonist. These studies demonstrate the potential benefit of XIAP to correct heart failure after highly efficient delivery to the heart with the rationally designed SASTG AAV vector.

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Section: Discussionmentioning

confidence: 99%

X-Linked Inhibitor of Apoptosis Protein-Mediated Attenuation of Apoptosis, Using a Novel Cardiac-Enhanced Adeno-Associated Viral Vector

et al. 2012

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“…Over the last several decades, tremendous progress has been made in delivering therapeutic genes to the heart (Kratlian and Hajjar, 2012;Wasala et al, 2011). A number of complicated techniques have been developed to transduce the myocardium by direct injection (to the myocardium or ventricular cavity), pericardial injection, coronary perfusion, and aorta injection using a variety of viral and nonviral vectors (Ishikawa et al, 2011;Katz et al, 2011;Wasala et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Long-Term Robust Myocardial Transduction of the Dog Heart from a Peripheral Vein by Adeno-Associated Virus Serotype-8

et al. 2013

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Molecular intervention using noninvasive myocardial gene transfer holds great promise for treating heart diseases. Robust cardiac transduction from peripheral vein injection has been achieved in rodents using adenoassociated virus (AAV) serotype-9 (AAV-9). However, a similar approach has failed to transduce the heart in dogs, a commonly used large animal model for heart diseases. To develop an effective noninvasive method to deliver exogenous genes to the dog heart, we employed an AAV-8 vector that expresses human placental alkaline phosphatase reporter gene under the transcriptional regulation of the Rous sarcoma virus promoter.

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“…These findings as well as results from several other labs strongly support the strategy of cardiac gene therapy for heart failure based on restoring appropriate Ca 2+ handling [42][43][44]. At this stage, one should cite the pioneering work led by Hajjar that led to a clinical trial (CUPID) using an expression cassette coding for SERCA2a [45]. This phase IIa study retained some intrinsic limitations due to the low number of patients.…”

Section: Heart Failurementioning

confidence: 65%

Gene Therapy for Cardiomyopathies

Fromes¹,

Roques²

2019

In Vivo and Ex Vivo Gene Therapy for Inherited and Non-Inherited Disorders

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Heart disease remains the prevalent cause of premature death and accounts for a significant proportion of all hospital admissions. Molecular genetics was integrated quite late in cardiology, but introduced new concepts like sarcolemmopathies, cytoskeletalopathies, and channelopathies useful to better understand the pathophysiology of the development of inherited cardiomyopathies (CMs). As our understanding of the cellular and molecular processes involved in the development and progression of heart disease improved, new therapeutic targets were identified, as were novel approaches such as delivery of genes to replace defective or deficient components and thereby restore structure or function in a diseased heart. We discuss gene addition strategies in the context of monogenic disorders. Moreover, a broader nucleic acid-based modulation of cardiac gene expression for the treatment of cardiac diseases might have larger clinical indications. Inadequate gene delivery remains a potential cause of negative trials. However, progress in innovative formulations and clinically relevant ways of administration should lead to significant progress in the future. Cardiac gene therapy will be integrated into the therapeutic armamentarium for CM and heart failure.

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Cardiac Gene Therapy: From Concept to Reality

Cited by 10 publications

References 49 publications

X-Linked Inhibitor of Apoptosis Protein-Mediated Attenuation of Apoptosis, Using a Novel Cardiac-Enhanced Adeno-Associated Viral Vector

X-Linked Inhibitor of Apoptosis Protein-Mediated Attenuation of Apoptosis, Using a Novel Cardiac-Enhanced Adeno-Associated Viral Vector

Long-Term Robust Myocardial Transduction of the Dog Heart from a Peripheral Vein by Adeno-Associated Virus Serotype-8

Gene Therapy for Cardiomyopathies

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