Phenotyping Cardiac Gene Therapy in Mice

Bostick, Brian; Yue, Yongping; Duan, Dongsheng

doi:10.1007/978-1-61737-982-6_6

Cited by 21 publications

(30 citation statements)

References 25 publications

(21 reference statements)

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“…To study cardiac electrophysiology, we performed 12-lead ECG recordings using our published protocol [30, 31]. Compared with BL6, mdx4cv showed characteristic dystrophic ECG changes such as tachycardia, PR-interval reduction, QRS duration and QT interval prolongation, and a significant increase in the cardiomyopathy index (Figure 3) [24, 28, 32, 33].…”

Section: Resultsmentioning

confidence: 99%

“…We next examined the pump function of the heart using an ultra-miniature Millar ventricular catheter [30, 31]. Compared with BL6, mdx4cv showed the characteristic profile of dilated cardiomyopathy (Figure 4) .…”

Section: Resultsmentioning

confidence: 99%

“…A 12-lead ECG assay was performed using a commercial system from AD Instruments (Colorado Springs, CO) according to our previously published protocol [30, 31]. The Q wave amplitude was determined using the lead I tracing.…”

Section: Methodsmentioning

confidence: 99%

“…Left ventricular hemodynamics was evaluated using a Millar ultra-miniature pressure–volume (PV) catheter SPR 839. The catheter was placed in the left ventricle using a closed chest approach as we have previously described [30, 31]. The resulting PV loops were analyzed with the PVAN software (Millar Instruments, Houston, TX).…”

Section: Methodsmentioning

confidence: 99%

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Uniform low-level dystrophin expression in the heart partially preserved cardiac function in an aged mouse model of Duchenne cardiomyopathy

Wasala

Yue

Vance

et al. 2017

Journal of Molecular and Cellular Cardiology

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Dystrophin deficiency results in Duchenne cardiomyopathy, a primary cause of death in Duchenne muscular dystrophy (DMD). Gene therapy has shown great promise in ameliorating the cardiac phenotype in mouse models of DMD. However, it is not completely clear how much dystrophin is required to treat dystrophic heart disease. We and others have shown that mosaic dystrophin expression at the wild-type level, depending on the percentage of dystrophin positive cardiomyocytes, can either delay the onset of or fully prevent cardiomyopathy in dystrophin-null mdx mice. Many gene therapy strategies will unlikely restore dystrophin to the wild-type level in a cardiomyocyte. To determine whether low-level dystrophin expression can reduce the cardiac manifestations in DMD, we examined heart histology, ECG and hemodynamics in 21-mold normal BL6 and two strains of BL6-background dystrophin-deficient mice. Mdx3cv mice show uniform low-level expression of a near full-length dystrophin protein in every myofiber while mdx4cv mice have no dystrophin expression. Immunostaining and western blot confirmed marginal level dystrophin expression in the heart of mdx3cv mice. Although low-level expression did not reduce myocardial histopathology, it significantly ameliorated QRS prolongation and normalized diastolic hemodynamic deficiencies. Our study demonstrates for the first time that low-level dystrophin can partially preserve heart function.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Uniform low-level dystrophin expression in the heart partially preserved cardiac function in an aged mouse model of Duchenne cardiomyopathy

Wasala

Yue

Vance

et al. 2017

Journal of Molecular and Cellular Cardiology

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“…All groups, except the controls were first trained and acclimated to the treadmill over a 1-week period (Bostick et al 2011) using a six track mouse treadmill (Exer-3/6 treadmill, Columbus Instruments, Ohio). The mice exercised five times per week during the next 8 weeks.…”

Section: Exercise Protocolmentioning

confidence: 99%

Chronic β2 adrenergic agonist, but not exercise, improves glucose handling in older type 2 diabetic mice

et al. 2012

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Insulin resistant type 2 diabetes mellitus in the obese elderly has become a worldwide epidemic. While exercise can prevent the onset of diabetes in young subjects its role in older diabetic people is less clear. Exercise stimulates the release of the β(2)-agonist epinephrine more in the young. Although epinephrine and β(2)-agonist drugs cause acute insulin resistance, their chronic effect on insulin sensitivity is unclear. We fed C57BL/6 mice a high fat diet to induce diabetes. These overweight animals became very insulin resistant. Exhaustive treadmill exercise 5 days a week for 8 weeks had no effect on their diabetes, nor did the β(2)-blocking drug ICI 118551. In contrast, exercise combined with the β(2)-agonist salbutamol (albuterol) had a beneficial effect on both glucose tolerance and insulin sensitivity after 4 and 8 weeks of exercise. The effect was durable and persisted 5 weeks after exercise and β(2)-agonist had stopped. To test whether β(2)-agonist alone was effective, the animals that had received β(2)-blockade were then given β(2)-agonist. Their response to a glucose challenge improved but their response to insulin was not significantly altered. The β(2)-agonists are commonly used to treat asthma and asthmatics have an increased incidence of obesity and type 2 diabetes. Although β(2)-agonists cause acute hyperglycemia, chronic treatment improves insulin sensitivity, probably by improving muscle glucose uptake.

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A Five-Repeat Micro-Dystrophin Gene Ameliorated Dystrophic Phenotype in the Severe DBA/2J-mdx Model of Duchenne Muscular Dystrophy

Hakim¹,

Wasala²,

Pan³

et al. 2017

Molecular Therapy - Methods & Clinical Development

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Micro-dystrophins are highly promising candidates for treating Duchenne muscular dystrophy, a lethal muscle disease caused by dystrophin deficiency. Here, we report robust disease rescue in the severe DBA/2J-mdx model with a neuronal nitric oxide synthase (nNOS)-binding micro-dystrophin vector. 2 × 1013 vector genome particles/mouse of the vector were delivered intravenously to 10-week-old mice and were evaluated at 6 months of age. Saturated micro-dystrophin expression was detected in all skeletal muscles and the heart and restored the dystrophin-associated glycoprotein complex and nNOS. In skeletal muscle, therapy substantially reduced fibrosis and calcification and significantly attenuated inflammation. Centronucleation was significantly decreased in the tibialis anterior (TA) and extensor digitorum longus (EDL) muscles but not in the quadriceps. Muscle function was normalized in the TA and significantly improved in the EDL muscle. Heart histology and function were also evaluated. Consistent with the literature, DBA/2J-mdx mice showed myocardial calcification and fibrosis and cardiac hemodynamics was compromised. Surprisingly, similar myocardial pathology and hemodynamic defects were detected in control DBA/2J mice. As a result, interpretation of the cardiac data proved difficult due to the confounding phenotype in control DBA/2J mice. Our results support further development of this microgene vector for clinical translation. Further, DBA/2J-mdx mice are not good models for Duchenne cardiomyopathy.

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Phenotyping Cardiac Gene Therapy in Mice

Cited by 21 publications

References 25 publications

Uniform low-level dystrophin expression in the heart partially preserved cardiac function in an aged mouse model of Duchenne cardiomyopathy

Uniform low-level dystrophin expression in the heart partially preserved cardiac function in an aged mouse model of Duchenne cardiomyopathy

Chronic β2 adrenergic agonist, but not exercise, improves glucose handling in older type 2 diabetic mice

A Five-Repeat Micro-Dystrophin Gene Ameliorated Dystrophic Phenotype in the Severe DBA/2J-mdx Model of Duchenne Muscular Dystrophy

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