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December 20, 2011

Nerve growth factor gene therapy could prevent diabetic heart disease

New research has investigated if nerve growth factor (NGF) gene therapy can prevent diabetic heart failure and small vascular disease in mice.

The team investigated whether increasing the myocardial level of NGF by using adeno-associated viral (AAV) vectors could prevent the diabetic heart from failure. AAVs are small non-enveloped, single-stranded DNA viruses that can potentially infect all cell types. They exist in different forms, allowing to better target different cells for gene therapy, including after AAV injection in a vein. Importantly, at variance from more popular viral vectors, AAVs allow for virtually permanent increased level of a therapeutic protein.

Professor Emanueli said: “Our study represents a major advance in tackling heart disease in diabetics, a leading cause of death in the western world. It also represents one important step forward in our goal for translating NGF-based therapies in cardiovascular patients.

25.8 million children and adults in the United States—8.3% of the population—have diabetes.

* 79 million people are pre-diabetic.

* 1.9 million new cases of diabetes are diagnosed in people aged 20 years and older in 2010.

* In 2004, heart disease was noted on 68% of diabetes-related death certificates among people aged 65 years or older.

* In 2004, stroke was noted on 16% of diabetes-related death certificates among people aged 65 years or older.

* Adults with diabetes have heart disease death rates about 2 to 4 times higher than adults without diabetes.

In 2007, diabetes was listed as the underlying cause on 71,382 death certificates and was listed as a contributing factor on an additional 160,022 death certificates. This means that diabetes contributed to a total of 231,404 deaths.




The researchers found diabetes lowered the cardiac expression of endogenous NGF mRNA. A progressive deterioration of cardiac function and left ventricular chamber dilatation appeared in β-Gal–treated diabetic mice. At 12 weeks of diabetes, β-Gal–treated mice showed myocardial microvascular rarefaction, hypoperfusion, more interstitial fibrosis and increased apoptosis of endothelial cells and cardiomyocytes. NGF gene therapy using either AAV2 or AAV9 prevented diabetes-induced cardiac dysfunction, reduced cardiac apoptosis and preserved cardiac microvasculature and blood flow.

The research results suggest that NGF gene therapy might have a tremendous therapeutic potential for the treatment of diabetic cardiomyopathy and encourage further translational efforts for the final benefit of diabetic patients.

However, before this gene therapy approach can be trialled in patients, additional pre-clinical studies need to be performed in order to verify not only the efficiency and the safety of AAVs-mediated NGF in type 1 diabetes, but also to find the most efficient AAV serotype, as well as the optimal dose and delivery route to be used.

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