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Adeno-Associated Virus-Mediated Delivery of CRISPR for Cardiac Gene Editing in Mice
Published on: August 2, 2018
SERCA2a gene transfer improves electrocardiographic performance in aged mdx mice
Jin-Hong Shin1, Brian Bostick, Yongping Yue
1Department of Molecular Microbiology and Immunology, School of Medicine, The University of Missouri, Columbia, MO, USA.
Background:
Cardiomyocyte calcium overloading has been implicated in the pathogenesis of Duchenne muscular dystrophy (DMD) heart disease. The cardiac isoform of sarcoplasmic reticulum calcium ATPase (SERCA2a) plays a major role in removing cytosolic calcium during heart muscle relaxation. Here, we tested the hypothesis that SERCA2a over-expression may mitigate electrocardiography (ECG) abnormalities in old female mdx mice, a murine model of DMD cardiomyopathy.
Methods:
1 × 10(12) viral genome particles/mouse of adeno-associated virus serotype-9 (AAV-9) SERCA2a vector was delivered to 12-m-old female mdx mice (N = 5) via a single bolus tail vein injection. AAV transduction and the ECG profile were examined eight months later.
Results:
The vector genome was detected in the hearts of all AAV-injected mdx mice. Immunofluorescence staining and western blot confirmed SERCA2a over-expression in the mdx heart. Untreated mdx mice showed characteristic tachycardia, PR interval reduction and QT interval prolongation. AAV-9 SERCA2a treatment corrected these ECG abnormalities.
Conclusions:
Our results suggest that AAV SERCA2a therapy may hold great promise in treating dystrophin-deficient heart disease.
Insights
Gene therapy using adeno-associated virus (AAV) to over-express SERCA2a corrected heart rhythm abnormalities in a mouse model of Duchenne muscular dystrophy (DMD). This suggests a potential treatment for DMD-related heart disease.
Area of Science:
- Cardiovascular Research
- Gene Therapy
- Muscular Dystrophy Research
Background:
- Duchenne muscular dystrophy (DMD) is linked to heart problems caused by too much calcium in heart cells.
- Sarcoplasmic reticulum calcium ATPase (SERCA2a) is crucial for managing calcium levels during heart relaxation.
Purpose of the Study:
- To investigate if over-expressing SERCA2a can reduce electrocardiography (ECG) abnormalities in female mdx mice, a model for DMD cardiomyopathy.
Main Methods:
- Female mdx mice received a single tail vein injection of adeno-associated virus serotype-9 (AAV-9) carrying the SERCA2a gene.
- Cardiac function and ECGs were assessed eight months post-injection.
Main Results:
- AAV-9 vector successfully delivered the SERCA2a gene to the heart, leading to its over-expression.
- Mice treated with AAV-9 SERCA2a showed corrected ECG abnormalities, including heart rate, PR interval, and QT interval.
Conclusions:
- Adeno-associated virus (AAV) mediated SERCA2a gene therapy shows promise for treating heart conditions in Duchenne muscular dystrophy.
- This therapeutic approach may offer a new strategy for managing dystrophin-deficient heart disease.
