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First-Time Experimental Gene Transfer Improves Hypertriglyceridemia

April, 2013 – A groundbreaking new study by American Heart Association Post-Doctoral Fellow Vineeta Sharma, CHORI scientists Robert Ryan, PhD, Gordon Watson, PhD, Trudy Forte, PhD, and their colleagues,  published in Arteriosclerosis, Thrombosis and Vascular Biology, demonstrates for the first time that APOA5 gene transfer using an adeno-associated virus significantly lowers plasma triacylglycerol (TG) levels in apoa5 (-/-) mice that manifest severely elevated TG levels. Elevated TG levels dramatically increase the risk for metabolic diseases, including diabetes, heart disease, and the so-called metabolic syndrome.

“We were able to impact TG levels for up to 8 weeks, which is very exciting, and very promising,” says Dr. Ryan. “While we still have many hurdles to overcome before this kind of gene therapy could be used clinically, it is certainly a step in that direction, and in the mean time, provides us with a very powerful research tool.”
“While we still have many hurdles to overcome before this kind of gene therapy could be used clinically, it is certainly a step in that direction, and in the mean time, provides us with a very powerful research tool.”



Apolipoprotein A-V (apoA-V) is a low abundance protein discovered in 2001 synthesized only in liver and secreted into the plasma, where it is found in association with plasma lipoproteins. Researchers believe that apoA-V facilitates the break down of circulating lipoproteins, promoting hydrolysis and utilization of the lipid cargo they carry. In human populations, certain subtle genetic variations in the APOA5 gene, called single nucleotide polymorphisms (SNPs), strongly correlate with elevated TG levels.

"When the apoA-V protein is defective, plasma TG concentrations go much higher," says Dr. Ryan. "In apoa5 knockout mice, in which the gene is engineered to be entirely absent, TG levels mimic those seen in patients with severely elevated TG levels, otherwise termed hypertriglyceridemia, which is associated with a host of metabolic disorders, such as diabetes and heart disease."

In the new study, Drs. Sharma, Ryan, and colleagues injected apoa5 knockout mice with an adeno-associated virus that included the coding sequence for human apoA-V or a control protein. Adeno-associated viruses allow for the expression of foreign protein in a host and, in this case, the expression of the apoA-V protein in a mouse.

The results were dramatic, with apoA-V expression levels in the physiological range.. This is important because it indicates that overexpression of apoA-V is not necessary to improve the TG phenotype.

"Of course the long-term vision would be potentially using this kind of gene therapy to treat human subjects that harbor APOA5 SNP's that cause defective apoA-V protein function. At the present time, however, the risks of still outweigh the benefits." says Dr. Ryan.

Now that Drs. Sharma, Ryan and colleagues have confirmed that the genetic code they expressed in these mice did in fact result in the production of the apoA-V protein and subsequent reductions in TG levels, they can now investigate the mechanism by which this protein functions.

“Using APOA5-engineered adeno-associated virus technology provides us with a powerful new research tool to better understand apoA-V function and mechanism.”

. "If we can now identify precisely how the apoA-V protein functions, and learn why certain variants are defective, we could potentially identify new treatment methods to control plasma TG levels, and thus lower the risk of metabolic disorders that affect the quality of life and health of millions of Americans," says Dr. Ryan.

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Monday, May 20, 2013 3:20 PM

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