scholarly journals Adeno-Associated Virus Serotype 6 Capsid Tyrosine-to-Phenylalanine Mutations Improve Gene Transfer to Skeletal Muscle

2010 ◽  
Vol 21 (10) ◽  
pp. 1343-1348 ◽  
Author(s):  
Chunping Qiao ◽  
Wei Zhang ◽  
Zhenhua Yuan ◽  
Jin-Hong Shin ◽  
Jianbin Li ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Gene Transfer ◽  
Adeno Associated Virus ◽  
Virus Serotype

Abstract 321: Cardiac Function Improvement Following In vivo Intracoronary Adeno-Associated Virus Type 1 Vector Gene Transfer of SERCA2a in a Pre-Clinical Model of Heart Failure

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Hung Q Ly ◽  
Yoshiaki Kawase ◽  
Fabrice A Prunier ◽  
Djamel Lebeche ◽  
Yafen Shi ◽  
...  
Keyword(s):  
Gene Transfer ◽  
Ventricular Remodeling ◽  
Systolic Function ◽  
Left Ventricular ◽  
Internal Diameter ◽  
Adeno Associated Virus ◽  
Inotropic Effects ◽  
Clinical Model ◽  
Virus Serotype

Background: Reduced activity and expression of sarcoplasmic reticulum Ca 2+ ATPase (SERCA2a) is known to occur in HF. Method: Our 4-month study examined the effects of SERCA2a gene transfer in a swine volume-overload HF (VO-HF) model. Using Yorkshire-Landrace swine, HF was created by severing mitral apparatus chordae to induce mitral regurgitation. Results: At 2 months (M), a compensated state of VO-HF was found: prolongation of the rate of isovolumic relaxation (Tau), increased left ventricular internal diameter diastolic and systolic diameters (LVIDd, LVIDs). At 2M, intracoronary injection of adeno-associated virus serotype 1 vector carrying SERCA2a under a cytomegalovirus promoter (AAV1.SERCA2a) (n = 10) vs. saline (n = 6) was performed. At 4M, gene transfer resulted in (A) positive LV inotropic effects: (dP/dt)/P, 15.5 ± 3.0 sec − 1 SERCA2a-group vs. 21.2 ± 3.2 sec − 1 controls; p < 0.01; (B) a favorable trend in LV lusitropic effects: Tau, 0.037 ± 0.019 vs. 0.051 ± 0.01 msec, p = 0.09; (C) improvement in LV geometry: % change in LVIDs, +15 ± 11% controls vs. −3.0 ± 10% SERCA2a-group, p < 0.01. At 4M, BNP levels remained stable in post- SERCA2a gene transfer, in contrast to the progressive rising levels among controls. Further, cardiac SERCA2a expression was significantly decreased in controls whereas it was restored to normal levels in the SERCA2a group (Figure ). Lastly, there was no histopathological evidence of myocardial inflammatory reaction or necrosis. Conclusion: Overexpression of SERCA2a by in vivo AAV1-mediated intracoronary gene transfer preserved systolic function, potentially prevented diastolic dysfunction and improved ventricular remodeling.

Systemic AAV9.LAMP2B injection reverses metabolic and physiologic multiorgan dysfunction in a murine model of Danon disease

2020 ◽  
Vol 12 (535) ◽  
pp. eaax1744 ◽  
Author(s):  
Ana Maria Manso ◽  
Sherin I. Hashem ◽  
Bradley C. Nelson ◽  
Emily Gault ◽  
Angel Soto-Hermida ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Gene Transfer ◽  
Murine Model ◽  
Autophagic Flux ◽  
Adeno Associated Virus ◽  
Multiorgan Dysfunction ◽  
Danon Disease ◽  
Physiologic Function ◽  
Male Patients ◽  
Dose Dependent

Danon disease (DD) is a rare X-linked autophagic vacuolar myopathy associated with multiorgan dysfunction, including the heart, skeletal muscle, and liver. There are no specific treatments, and most male patients die from advanced heart failure during the second or third decade of life. DD is caused by mutations in the lysosomal-associated membrane protein 2 (LAMP2) gene, a key mediator of autophagy. LAMP2 has three isoforms: LAMP2A, LAMP2B, and LAMP2C. LAMP2B is the predominant isoform expressed in cardiomyocytes. This study evaluates the efficacy of human LAMP2B gene transfer using a recombinant adeno-associated virus 9 carrying human LAMP2B (AAV9.LAMP2B) in a Lamp2 knockout (KO) mouse, a DD model. AAV9.LAMP2B was intravenously injected into 2- and 6-month-old Lamp2 KO male mice to assess efficacy in adolescent and adult phenotypes. Lamp2 KO mice receiving AAV9.LAMP2B demonstrated dose-dependent restoration of human LAMP2B protein in the heart, liver, and skeletal muscle tissue. Impaired autophagic flux, evidenced by increased LC3-II, was abrogated by LAMP2B gene transfer in all tissues in both cohorts. Cardiac function was also improved, and transaminases were reduced in AAV9.LAMP2B-treated KO mice, indicating favorable effects on the heart and liver. Survival was also higher in the older cohort receiving high vector doses. No anti-LAMP2 antibodies were detected in mice that received AAV9.LAMP2B. In summary, LAMP2B gene transfer improves metabolic and physiologic function in a DD murine model, suggesting that a similar therapeutic approach may be effective for treating patients with this highly morbid disease.

scholarly journals A Single Intravenous Injection of Adeno-associated Virus Serotype-9 Leads to Whole Body Skeletal Muscle Transduction in Dogs

2008 ◽  
Vol 16 (12) ◽  
pp. 1944-1952 ◽  
Author(s):  
Yongping Yue ◽  
Arkasubhra Ghosh ◽  
Chun Long ◽  
Brian Bostick ◽  
Bruce F Smith ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Intravenous Injection ◽  
Whole Body ◽  
Adeno Associated Virus ◽  
Single Intravenous Injection ◽  
Virus Serotype

scholarly journals Supraspinal gene transfer by intrathecal adeno-associated virus serotype 5

2014 ◽  
Vol 8 ◽  
Author(s):  
Daniel J. Schuster ◽  
Lalitha R. Belur ◽  
Maureen S. Riedl ◽  
Stephen A. Schnell ◽  
Kelly M. Podetz-Pedersen ◽  
...  
Keyword(s):  
Gene Transfer ◽  
Adeno Associated Virus ◽  
Virus Serotype ◽  
Serotype 5

Stabilized HIF‐1α is superior to VEGF for angiogenesis in skeletal muscle via adeno‐associated virus gene transfer

2005 ◽  
Vol 19 (10) ◽  
pp. 1365-1367 ◽  
Author(s):  
Katri Pajusola ◽  
Jaana Künnapuu ◽  
Sanna Vuorikoski ◽  
Jarkko Soronen ◽  
Helder André ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Gene Transfer ◽  
Adeno Associated Virus ◽  
Virus Gene

scholarly journals Structure of Adeno-Associated Virus Vector DNA following Transduction of the Skeletal Muscle

1999 ◽  
Vol 73 (3) ◽  
pp. 1949-1955 ◽  
Author(s):  
Nathalie Vincent-Lacaze ◽  
Richard O. Snyder ◽  
Régis Gluzman ◽  
Delphine Bohl ◽  
Catherine Lagarde ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Gene Transfer ◽  
Transgene Expression ◽  
De Novo ◽  
Early Time ◽  
Progressive Increase ◽  
Stable Gene ◽  
Adeno Associated Virus ◽  
Rolling Circle ◽  
Time Points

ABSTRACT The skeletal muscle provides a very permissive physiological environment for adeno-associated virus (AAV) type 2-mediated gene transfer. We have studied the early steps leading to the establishment of permanent transgene expression, after injection of recombinant AAV (rAAV) particles in the quadriceps muscle of mice. The animals received an rAAV encoding a secreted protein, murine erythropoietin (mEpo), under the control of the human cytomegalovirus major immediate-early promoter and were sacrificed between 1 and 60 days after injection. The measurement of plasma Epo levels and of hematocrits indicated a progressive increase of transgene expression over the first 2 weeks, followed by a stabilization at maximal plateau values. The rAAV sequences were analyzed by Southern blotting following neutral or alkaline gel electrophoresis of total DNA from injected muscles. While a high number of rAAV sequences were detected during the first 5 days following the injection, only a few percent of these sequences was retained in the animals analyzed after 2 weeks, in which transgene expression was maximal. Double-stranded DNA molecules resulting from de novo second-strand synthesis were detected as early as day 1, indicating that this crucial step of AAV-mediated gene transfer is readily accomplished in the muscle. The templates driving stable gene expression at later time points are low in copy number and structured as high-molecular-weight concatemers or interlocked circles. The presence of the circular form of the rAAV genomes at early time points suggests that the molecular transformations involved in the formation of stable concatemers may involve a rolling-circle type of DNA replication.

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