VIRxSYS is investigating a highly innovative approach to raise the plasma levels of high density lipoproteins or HDL (also known as the “good cholesterol”). HDL has many anti-atherosclerotic effects, the most important being reverse cholesterol transport, or removing cholesterol from arterial walls and reducing plaque formation, thus reducing the related inflammatory and rupturing potential of the plaque, eventually leading to less acute ischemic heart attacks. HDL levels have been predicted as one of the best indicators of atherosclerosis risk. The Company’s strategy to increase HDL levels is based on the de novo and in situ production of the major protein component of HDL: the apolipoprotein A-I (apoA-I). ApoA-I is normally produced in hepatocytes (liver cells) and the small intestine.
HDL is commonly referred to as “good cholesterol” because higher levels of this protein are generally associated with healthier cardiovascular systems, and lower risk for heart attack. Conversely, lower blood levels of HDL may represent an important risk indicator of cardiovascular disease. Recent research suggests that existing LDL (low density lipoproteins) lowering drugs are probably not the final answer in combating heart diseases [1]. There currently are very limited FDA approved therapy options in the area of increasing HDL.
The current number of people with HDL deficiency or low level is estimated to be approximately 100 million people worldwide. These individuals could naturally benefit from HDL enhancement therapy [2,3]. In just the United States, the American Heart Association estimated that 33.9 million Americans have HDL levels below the recommended levels of 35-40mg/dl [4]. Epidemiologic data showed that an increase of 1 mg/dl in plasma HDL represented a 2 and 3% decrease in risk of cardiovascular disease in men and women, respectively [5].
VIRxSYS’ innovative therapeutic approach is based on the reprogramming properties of VIRxSYS’ SMaRTTM technology. This approach essentially turns the very abundant gene transcripts from the albumin gene, produced in hepatocytes, into new transcripts encoding for the apoA-I proteins. This approach has several advantages over conventional gene therapy and small-drug based therapies. Because the PTM coding for apoA-I is highly specific to albumin gene transcripts (pre-mRNA), only the cells expressing albumin gene transcripts after transduction with VIRxSYS’ lentiviral vector construct expressing the human apoA-I PTM would be capable of producing de novo and in situ extra human apoA-I proteins. Because the production of the new, extra apoA-I proteins will be limited to the human cells that normally produce this protein, issues normally associated with conventional gene therapy approaches, such as immune reaction against the newly synthesized protein, should be avoided. Importantly, this biological approach is predicted to be less toxic than conventional small drug approaches, where the small molecules usually interfere with normal enzymatic process in the liver, sometimes with severe liver toxicities.
VIRxSYS has integrated its SMaRT™ technology for HDL with the Company’s lentiviral vector delivery technology to produce a human product candidate VRX1243. VIRxSYS has collaborated with the National Heart, Lung and Blood Institute (NHLBI) of the National Institutes of Health (NIH) through a Cooperative Research and Development Agreement (CRADA). In a collaborative study published in a peer-reviewed scientific journal [6], VIRxSYS and the NHLBI delivered into mouse hepatocytes SMaRT™ PTMs encoding for human apoA-I. This resulted in significantly increased plasma levels of both human apoA-I proteins and ultimately total HDL in those mice.
Through the existing CRADA with the NHLBI, the Company is in the process of assessing the safety and efficacy of VRX1243 in larger non-human primates.
Based on the upcoming non-human primate studies, the Company expects to determine a proposed injection regimen of the VIRxSYS HDL therapy for humans. This therapy has the potential to produce a significant increase in HDL, which should promote cholesterol reverse-transport, remove cholesterol deposits from arterial walls, and reduce additional plaque formation. The initial clinical application for VRX1243, likely through a Clinical Trial Agreement (CTA) with the NHLBI, will be the treatment of individuals unable to produce apoA-I proteins, and thus making that patient population very high-risk for developing fatal cardiovascular episodes at a young age.
References:
[1] Business Week March 12th 2010
[2] Intensive Statin Therapies – A Sea Change in Cardiovascular Prevention. Topol, E.J., New England Journal of Medicine, Editorial, April 8, 2004 (http://my.clevelandclinic.org/Documents/heart/NEJMe048061v1.pdf)
[3] Wall Street Journal, November 4, 2003
[4] AHA 2009 Update (http://circ.ahajournals.org/cgi/reprint/119/3/e21.pdf)
[5] Gordon et al. High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies. Circulation, 79(1):8-15, 1989. (http://circ.ahajournals.org/cgi/reprint/79/1/8.pdf)
[6] Wang et al. Trans-splicing into highly abundant albumin transcripts for production of therapeutic proteins in vivo. Molecular Therapy, 17(2):343-51, 2009. (http://www.nature.com/mt/journal/v17/n2/pdf/mt2008260a.pdf)