Efficiency of eight different AAV serotypes in transducing rat myocardium in vivo

Palomeque, Julieta; Chemaly, Elie R.; Colosi, Peter; Wellman, Jennifer; Zhou, Shang Zhen; Monte, Federica del; Hajjar, Roger J.

doi:10.1038/sj.gt.3302895

Cited by 110 publications

(94 citation statements)

References 50 publications

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“…17 Onset of transgene expression from AAV6 in rat has been reported to be evident from 1 week postgene delivery, significantly increasing by 4 weeks and maximal by 12 weeks postgene delivery. 35 The temporal profile of rAAV6:ACE2 expression thus correlates with the echocardiography data in the present study, with deterioration of cardiac function being visible at 4 weeks postinfusion and greatest at the end point of 11 weeks postinfusion.…”

Section: Hypertension April 2009supporting

confidence: 85%

Onset of Experimental Severe Cardiac Fibrosis Is Mediated by Overexpression of Angiotensin-Converting Enzyme 2

et al. 2009

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Abstract-Angiotensin-converting enzyme (ACE) 2 is a recently identified homologue of ACE. There is great interest in the therapeutic benefit for ACE2 overexpression in the heart. However, the role of ACE2 in the regulation of cardiac structure and function, as well as maintenance of systemic blood pressure, remains poorly understood. In cell culture, ACE2 overexpression led to markedly increased myocyte volume, assessed in primary rabbit myocytes. To assess ACE2 function in vivo, we used a recombinant adeno-associated virus 6 delivery system to provide 11-week overexpression of ACE2 in the myocardium of stroke-prone spontaneously hypertensive rats. ACE2, as well as the ACE inhibitor enalapril, significantly reduced systolic blood pressure. However, in the heart, ACE2 overexpression resulted in cardiac fibrosis, as assessed by histological analysis with concomitant deficits in ejection fraction and fractional shortening measured by echocardiography. Furthermore, global gene expression profiling demonstrated the activation of profibrotic pathways in the heart mediated by ACE2 gene delivery. This study demonstrates that sustained overexpression of ACE2 in the heart in vivo leads to the onset of severe fibrosis. (Hypertension. 2009;53:694-700.)Key Words: ACE2 Ⅲ gene delivery Ⅲ adeno-associated virus Ⅲ hypertension Ⅲ myocardium O veractivity of the renin-angiotensin (Ang) system plays a fundamental role in the pathophysiology of hypertension and progression of heart failure. 1 Ang-converting enzyme (ACE) 2 is a recently identified homologue of ACE, and their catalytic domains share 42% amino acid identity. 2-4 ACE2 expression is restricted to the heart, kidney, and testis. 2,5 After myocardial infarction, increased ACE2 expression in the heart localized to vascular endothelium, smooth muscle, and cardiomyocytes in both rats and humans. 6 Unlike ACE, ACE2 functions as a carboxypeptidase rather than a dipeptidyl carboxypeptidase 5 and counterbalances the vasopressor effects of ACE. 7 ACE2 primarily hydrolyzes Ang II and, less efficiently, Ang I, 2 resulting in Ang 1-7 and Ang 1-9. Ang 1-9 is further hydrolyzed to Ang 1-7 by the actions of ACE. 5 ACE inhibitors and Ang II receptor blockers are effective drugs for the treatment of cardiovascular diseases, as a result of blocking the vasoconstrictor, hypertrophic, and proinflammatory actions of Ang II. 8 -11 Thus, ACE2 may play a pivotal role in the renin-Ang system by reducing concentrations of Ang II and raising levels of Ang 1-7. 12,13 Therefore, manipulation of ACE2 activity has potential therapeutic use. However, ACE2 knockout mice have been associated with severe contractile dysfunction 14 or, conversely, with no observed effects on cardiac dimension or function. 15 Overexpression of ACE2 by local delivery of lentivirus in the hearts of spontaneously hypertensive rats attenuated high blood pressure (BP) and perivascular fibrosis, reduced left ventricular (LV) wall thickness, and increased LV end diastolic and end systolic diameters. 16 Conversely, transgenic overex...

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Section: Hypertension April 2009supporting

confidence: 85%

Onset of Experimental Severe Cardiac Fibrosis Is Mediated by Overexpression of Angiotensin-Converting Enzyme 2

et al. 2009

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“…Natural AAV1 and 6 are highly efficient in directly infecting striated muscles by local intramuscular (26,27) or intramyocardial injection (28,29), whereas AAV7, 8, and 9 are highly efficient in crossing the endothelial barriers in muscle and heart (5,6,30). To engineer vectors with combined properties, we generated AAV capsid gene libraries by DNA shuffling and performed direct in vivo selection.…”

Section: Discussionmentioning

confidence: 99%

A myocardium tropic adeno-associated virus (AAV) evolved by DNA shuffling and in vivo selection

Yang

Jiang

Drouin

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

188

164

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To engineer gene vectors that target striated muscles after systemic delivery, we constructed a random library of adeno-associated virus (AAV) by shuffling the capsid genes of AAV serotypes 1 to 9, and screened for muscle-targeting capsids by direct in vivo panning after tail vein injection in mice. After 2 rounds of in vivo selection, a capsid gene named M41 was retrieved mainly based on its high frequency in the muscle and low frequency in the liver. Structural analyses revealed that the AAVM41 capsid is a recombinant of AAV1, 6, 7, and 8 with a mosaic capsid surface and a conserved capsid interior. AAVM41 was then subjected to a sideby-side comparison to AAV9, the most robust AAV for systemic heart and muscle gene delivery; to AAV6, a parental AAV with strong muscle tropism. After i.v. delivery of reporter genes, AAVM41 was found more efficient than AAV6 in the heart and muscle, and was similar to AAV9 in the heart but weaker in the muscle. In fact, the myocardium showed the highest gene expression among all tissues tested in mice and hamsters after systemic AAVM41 delivery. However, gene transfer in non-muscle tissues, mainly the liver, was dramatically reduced. AAVM41 was further tested in a genetic cardiomyopathy hamster model and achieved efficient long-term ␦-sarcoglycan gene expression and rescue of cardiac functions. Thus, direct in vivo panning of capsid libraries is a simple tool for the de-targeting and retargeting of viral vector tissue tropisms facilitated by acquisition of desirable sequences and properties.

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“…AAV vectors have been widely used for cardiac gene transfer. Serotypes 1,6,7,8,and 9 (Table 3) appear to be the most efficient for transduction, although many of the newer less described serotypes may also efficiently transduce myocardial tissue (293,294,672,844). Depending on the exact capsid serotype and delivery method, AAV vectors have transduced nearly 100% of cardiac tissues (294,893).…”

Section: Direct Injection Restricted Transduction Increased Safetymentioning

confidence: 99%

Designing Heart Performance by Gene Transfer

Davis¹,

Westfall²,

Townsend³

et al. 2008

Physiological Reviews

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The birth of molecular cardiology can be traced to the development and implementation of high-fidelity genetic approaches for manipulating the heart. Recombinant viral vector-based technology offers a highly effective approach to genetically engineer cardiac muscle in vitro and in vivo. This review highlights discoveries made in cardiac muscle physiology through the use of targeted viral-mediated genetic modification. Here the history of cardiac gene transfer technology and the strengths and limitations of viral and nonviral vectors for gene delivery are reviewed. A comprehensive account is given of the application of gene transfer technology for studying key cardiac muscle targets including Ca2+handling, the sarcomere, the cytoskeleton, and signaling molecules and their posttranslational modifications. The primary objective of this review is to provide a thorough analysis of gene transfer studies for understanding cardiac physiology in health and disease. By comparing results obtained from gene transfer with those obtained from transgenesis and biophysical and biochemical methodologies, this review provides a global view of cardiac structure-function with an eye towards future areas of research. The data presented here serve as a basis for discovery of new therapeutic targets for remediation of acquired and inherited cardiac diseases.

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Efficiency of eight different AAV serotypes in transducing rat myocardium in vivo

Cited by 110 publications

References 50 publications

Onset of Experimental Severe Cardiac Fibrosis Is Mediated by Overexpression of Angiotensin-Converting Enzyme 2

Onset of Experimental Severe Cardiac Fibrosis Is Mediated by Overexpression of Angiotensin-Converting Enzyme 2

A myocardium tropic adeno-associated virus (AAV) evolved by DNA shuffling and in vivo selection

Designing Heart Performance by Gene Transfer

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