Efficient and Durable Gene Transfer to Transplanted Heart Using Adeno-associated Virus 9 Vector

Miyagi, Naoto; Rao, Vinay; Ricci, Davide; Du, Zeji; Byrne, Guerard W.; Bailey, Kent R.; Nakai, Hiroyuki; Russell, Stephen J.; McGregor, Christopher G.A.

doi:10.1016/j.healun.2008.01.025

Cited by 24 publications

(21 citation statements)

References 31 publications

(19 reference statements)

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“…We report here that AAV9 provides highly efficient, global gene transfer to the left ventricular free wall of the adult rat after direct injection into the myocardium in five equally spaced aliquots. This level of gene transfer exceeds that provided by the other serotypes evaluated by approximately 1 log and is superior to the gene transfer achieved by another investigator using a vascular delivery method (Miyagi et al, 2008). AAV9-mediated gene expression was also specific to the heart after direct injection.…”

Section: Discussionmentioning

confidence: 69%

Adeno-Associated Virus (AAV) Serotype 9 Provides Global Cardiac Gene Transfer Superior to AAV1, AAV6, AAV7, and AAV8 in the Mouse and Rat

et al. 2008

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Heart disease is the leading cause of morbidity and mortality. Cardiac gene transfer may serve as a novel therapeutic approach. This investigation was undertaken to compare cardiac tropisms of adeno-associated virus (AAV) serotypes 1, 6, 7, 8, and 9. Neonatal mice were injected with 2.5 ϫ 10 11 genome copies (GC) of AAV serotype 1, 6, 7, 8, or 9 expressing LacZ under the control of the constitutive chicken ␤-actin promoter with cytomegalovirus enhancer promoter via intrapericardial injection and monitored for up to 1 year. Adult rats were injected with 5 ϫ 10 11 GC of the AAV vectors via direct cardiac injection and monitored for 1 month. Cardiac distribution of LacZ expression was assessed by X-Gal histochemistry, and ␤-galactosidase activity was quantified in a chemiluminescence assay. Cardiac functional data and biodistribution data were also collected in the rat. AAV9 provided global cardiac gene transfer stable for up to 1 year that was superior to other serotypes. LacZ expression was relatively cardiac specific, and cardiac function was unaffected by gene transfer. AAV9 provides high-level, stable expression in the mouse and rat heart and may provide a simple alternative to the creation of cardiac-specific transgenic mice. AAV9 should be used in rodent cardiac studies and may be the vector of choice for clinical trials of cardiac gene transfer. 1359

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Section: Discussionmentioning

confidence: 69%

Adeno-Associated Virus (AAV) Serotype 9 Provides Global Cardiac Gene Transfer Superior to AAV1, AAV6, AAV7, and AAV8 in the Mouse and Rat

et al. 2008

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“…To ascertain whether the defects in βAR-induced cardiac performance are due to loss of Mdm2 expression that is independent of p53 deletion, we undertook an Mdm2 gene rescue approach using systemic transduction with AAV9 vectors, which produce substantial expression of target genes in cardiomyocytes in addition to other tissues such as liver and lungs (28)(29)(30)(31)(32). We assessed βAR responsiveness in Mdm2/p53-KO mice by invasive hemodynamics in control AAV9-GFP (GFP-rescue) and AAV9-Mdm2 (Mdm2-rescue) injected mice 21 days after AAV administration.…”

Section: Baseline Characteristics and Function Of Mdm2/p53-ko Mice Hementioning

confidence: 99%

Mdm2 regulates cardiac contractility by inhibiting GRK2-mediated desensitization of β-adrenergic receptor signaling

Jean-Charles¹,

Yu²,

Abraham³

et al. 2017

JCI Insight

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“…Conventional AAV vectors derived from AAV serotype 2 have a broad tissue tropism, which results in the predominant transduction of the liver after systemic vector administration. Newer AAV vectors derived from serotypes 1, 4, 5, 6, and 9 allow enhanced gene transfer into the myocardium [5,6]. Ex vivo perfusion of an AAV-9 vector into the donor heart achieved up to 72% myocardial gene transfer efficiency 10 days after heart transplantation in rodents [6].…”

Section: Mechanismmentioning

confidence: 99%

“…Newer AAV vectors derived from serotypes 1, 4, 5, 6, and 9 allow enhanced gene transfer into the myocardium [5,6]. Ex vivo perfusion of an AAV-9 vector into the donor heart achieved up to 72% myocardial gene transfer efficiency 10 days after heart transplantation in rodents [6]. Cardiac expression levels of the LacZ reporter gene were unchanged 3 months after transplantation, with no overt evidence of tissue toxicity.…”

Section: Mechanismmentioning

confidence: 99%

Modalities and future prospects of gene therapy in heart transplantation

Vassalli¹,

Roehrich²,

Vogt³

et al. 2009

European Journal of Cardio-Thoracic Surgery

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Heart transplantation is the treatment of choice for many patients with end-stage heart failure. Its success, however, is limited by organ shortage, side effects of immunosuppressive drugs, and chronic rejection. Gene therapy is conceptually appealing for applications in transplantation, as the donor organ is genetically manipulated ex vivo before transplantation. Localised expression of immunomodulatory genes aims to create a state of immune privilege within the graft, which could eliminate the need for systemic immunosuppression. In this review, recent advances in the development of gene therapy in heart transplantation are discussed. Studies in animal models have demonstrated that genetic modification of the donor heart with immunomodulatory genes attenuates ischaemia-reperfusion injury and rejection. Alternatively, bone marrow-derived cells genetically engineered with donor-type major histocompatibility complex (MHC) class I or II promote donor-specific hyporesponsiveness. Genetic engineering of naïve T cells or dendritic cells may induce regulatory T cells and regulatory dendritic cells. Despite encouraging results in animal models, however, clinical gene therapy trials in heart transplantation have not yet been started. The best vector and gene to be delivered remain to be identified. Pre-clinical studies in non-human primates are needed. Nonetheless, the potential of gene therapy as an adjunct therapy in transplantation is essentially intact.

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Efficient and Durable Gene Transfer to Transplanted Heart Using Adeno-associated Virus 9 Vector

Abstract: Background-We studied the efficacy and durability of recombinant adeno-associated virus serotype 9 (rAAV9) vector mediated gene transfer to the transplanted rat heart.

Cited by 24 publications

References 31 publications

Adeno-Associated Virus (AAV) Serotype 9 Provides Global Cardiac Gene Transfer Superior to AAV1, AAV6, AAV7, and AAV8 in the Mouse and Rat

Adeno-Associated Virus (AAV) Serotype 9 Provides Global Cardiac Gene Transfer Superior to AAV1, AAV6, AAV7, and AAV8 in the Mouse and Rat

Mdm2 regulates cardiac contractility by inhibiting GRK2-mediated desensitization of β-adrenergic receptor signaling

Modalities and future prospects of gene therapy in heart transplantation

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