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. 2008 Aug;19(8):851-6.
doi: 10.1089/hum.2008.058.

Adeno-associated virus serotype-9 microdystrophin gene therapy ameliorates electrocardiographic abnormalities in mdx mice

Brian Bostick  1 , Yongping Yue, Yi Lai, Chun Long, Dejia Li, Dongsheng Duan
Affiliations

Adeno-associated virus serotype-9 microdystrophin gene therapy ameliorates electrocardiographic abnormalities in mdx mice

Brian Bostick et al. Hum Gene Ther. 2008 Aug.

Abstract

Adeno-associated virus (AAV)-mediated microdystrophin gene therapy holds great promise for treating Duchenne muscular dystrophy (DMD). Previous studies have revealed excellent skeletal muscle protection. Cardiac muscle is also compromised in DMD patients. Here we show that a single intravenous injection of AAV serotype-9 (AAV-9) microdystrophin vector efficiently transduced the entire heart in neonatal mdx mice, a dystrophin-deficient mouse DMD model. Furthermore, microdystrophin therapy normalized the heart rate, PR interval, and QT interval. The cardiomyopathy index was also significantly improved in treated mdx mice. Our study demonstrates for the first time that AAV microdystrophin gene therapy can ameliorate the electrocardiographic abnormalities in a mouse model for DMD.

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Figures

FIG. 1.
FIG. 1.
A single intravenous AAV-9 injection leads to efficient microdystrophin expression throughout the entire heart. Representative immunofluorescence staining images of the mdx heart infected with AAV-9 microdystrophin vector (n = 12). mdx mice were infected at 1 day of age and immunofluorescence staining was performed 4 months after AAV infection with a human dystrophin-specific antibody. High-magnification photomicrographs for the left ventricle (LV), right ventricle (RV), and septum (Sep) were obtained from the respective boxed areas in the full-view image.
FIG. 2.
FIG. 2.
Neonatal AAV-9 microdystrophin therapy improves the ECG profile in young adult mdx mice. (A) Representative serial lead II tracings from mdx, AAV microgene-treated mdx, and BL10 mice. RR, the time interval between two QRS complexes. It is inversely correlated with the heart rate. The dotted lines denote the relative position of an RR interval in BL10 mice. (B) Representative single lead II tracing from mdx, AAV microgene-treated mdx, and BL10 mice. PR, the time interval between the onset of atrial depolarization and the onset of ventricular depolarization. QT, time interval between the onset of ventricular depolarization and the end of ventricular repolarization. The dotted lines denote the approximate positions of the PR and QT intervals. (C) ECG profiles from mdx, AAV microgene-treated mdx, and BL10 mice. *Significantly different from that of mdx (p < 0.04); **significantly different from that of mdx (p ≤ 0.001). Significant differences between BL10 and AAV-treated mdx are marked for HR, PR, QTc, and cardiomyopathy index. The QRS duration and the Q amplitude showed no significant difference among BL10, mdx, and AAV-treated mdx mice. HR, heart rate; PR, PR interval; QRS, QRS duration; QTc, heart rate-corrected QT interval; Q Amp, Q amplitude in lead I; C. Index, cardiomyopathy index.
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