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

Bish, Lawrence T.; Morine, Kevin; Sleeper, Margaret M.; Sanmiguel, Julio; Wu, Di; Gao, Guangping; Wilson, James M.; Sweeney, H. Lee

doi:10.1089/hum.2008.123

Cited by 246 publications

(190 citation statements)

References 32 publications

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“…Long-term expression of cMyBP-C in the heart was achieved by a single intravenous injection in 1-day-old KI mice using a combination of AAV9, which is the most cardiotropic serotype in rodents 21,36 and a cardiomyocyte-specific promoter 36,37 . Previous data indicated that combining AAV9 and a chicken minimal truncated TNNT2 promoter gave 4640-fold higher expression in the heart than in other organs in mice 37 .…”

Section: Discussionmentioning

confidence: 99%

Mybpc3 gene therapy for neonatal cardiomyopathy enables long-term disease prevention in mice

et al. 2014

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Homozygous or compound heterozygous frameshift mutations in MYBPC3 encoding cardiac myosin-binding protein C (cMyBP-C) cause neonatal hypertrophic cardiomyopathy (HCM), which rapidly evolves into systolic heart failure and death within the first year of life. Here we show successful long-term Mybpc3 gene therapy in homozygous Mybpc3-targeted knock-in (KI) mice, which genetically mimic these human neonatal cardiomyopathies. A single systemic administration of adeno-associated virus (AAV9)-Mybpc3 in 1-day-old KI mice prevents the development of cardiac hypertrophy and dysfunction for the observation period of 34 weeks and increases Mybpc3 messenger RNA (mRNA) and cMyBP-C protein levels in a dose-dependent manner. Importantly, Mybpc3 gene therapy unexpectedly also suppresses accumulation of mutant mRNAs. This study reports the first successful long-term gene therapy of HCM with correction of both haploinsufficiency and production of poison peptides. In the absence of alternative treatment options except heart transplantation, gene therapy could become a realistic treatment option for severe neonatal HCM.

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Section: Discussionmentioning

confidence: 99%

Mybpc3 gene therapy for neonatal cardiomyopathy enables long-term disease prevention in mice

et al. 2014

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“…One of the more interesting vectors is based on AAV9 that was isolated from human DNA (9). AAV9 has shown significant promise in targeting the heart for treatment of cardiomyopathies (12) and neurons for treating diseases such as spinal muscular atrophy (13,14). AAV9 also very efficiently transduces alveolar epithelial cells of the lung without eliciting a humoral response, allowing for efficient re-administration of vector (15).…”

Section: Introductionmentioning

confidence: 99%

The AAV9 receptor and its modification to improve in vivo lung gene transfer in mice

Bell

Vandenberghe²,

Bell³

et al. 2011

J. Clin. Invest.

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Vectors based on adeno-associated virus (AAV) serotype 9 are candidates for in vivo gene delivery to many organs, but the receptor(s) mediating these tropisms have yet to be defined. We evaluated AAV9 uptake by glycans with terminal sialic acids (SAs), a common mode of cellular entry for viruses. We found, however, that AAV9 binding increased when terminal SA was enzymatically removed, suggesting that galactose, which is the most commonly observed penultimate monosaccharide to SA, may mediate AAV9 transduction.

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“…CRISPR/Cas9 is a powerful genome-editing tool [16][17][18] and AAV9-mediated delivery preferentially targets cardiac cells [29][30][31]. We next attempted to combine these two approaches to target the PRKAG2 mutation associated with PRKAG2 cardiac syndrome.…”

Section: Specificity Of the Designed Crispr/cas9 Systemmentioning

confidence: 99%

Genome editing with CRISPR/Cas9 in postnatal mice corrects PRKAG2 cardiac syndrome

et al. 2016

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PRKAG2 cardiac syndrome is an autosomal dominant inherited disease resulted from mutations in the PRK-AG2 gene that encodes γ2 regulatory subunit of AMP-activated protein kinase. Affected patients usually develop ventricular tachyarrhythmia and experience progressive heart failure that is refractory to medical treatment and requires cardiac transplantation. In this study, we identify a H530R mutation in PRKAG2 from patients with familial Wolff-Parkinson-White syndrome. By generating H530R PRKAG2 transgenic and knock-in mice, we show that both models recapitulate human symptoms including cardiac hypertrophy and glycogen storage, confirming that the H530R mutation is causally related to PRKAG2 cardiac syndrome. We further combine adeno-associated virus-9 (AAV9) and the CRISPR/Cas9 gene-editing system to disrupt the mutant PRKAG2 allele encoding H530R while leaving the wild-type allele intact. A single systemic injection of AAV9-Cas9/sgRNA at postnatal day 4 or day 42 substantially restores the morphology and function of the heart in H530R PRKAG2 transgenic and knock-in mice. Together, our work suggests that in vivo CRISPR/Cas9 genome editing is an effective tool in the treatment of PRKAG2 cardiac syndrome and other dominant inherited cardiac diseases by selectively disrupting disease-causing mutations.

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

Cited by 246 publications

References 32 publications

Mybpc3 gene therapy for neonatal cardiomyopathy enables long-term disease prevention in mice

Mybpc3 gene therapy for neonatal cardiomyopathy enables long-term disease prevention in mice

The AAV9 receptor and its modification to improve in vivo lung gene transfer in mice

Genome editing with CRISPR/Cas9 in postnatal mice corrects PRKAG2 cardiac syndrome

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