Open Competition 5 - Biotechnology

Utilization of Small Interfering RNAs for Drug Target Validation In Vitro and In Vivo

Sponsor: Mirus Bio Corporation (formerly Mirus Corporation)

• Project Performance Period: 6/1/2002 - 5/31/2005
• Total project (est.): $2,927,040.00
• Requested ATP funds: $2,000,000.00

The average cost of developing one successful new drug is estimated at $880 million, of which 75 percent can be attributed to the many failed drug candidates. A key reason for the high failure rate is that, although vast libraries of candidates and screening tools are becoming available, pharmaceutical companies lack effective methods for identifying the protein that is the key therapeutic target for a particular disease. Proteins are expressed by genes through the action of an intermediate molecule called messenger RNA (mRNA). In a three-year project, Mirus Corporation plans to develop and demonstrate technology that will degrade specific mRNA molecules and thereby inhibit the expression of a specific gene both in cell cultures and in animals, enabling researchers to ascertain the biological effects and, eventually, validate drug targets effectively. The new technology will be based on double-stranded molecules called small interfering RNA (siRNA) (RNA usually has a single strand). Preliminary data show that Mirus's proprietary methods for delivering genes into mammalian cells allow for the delivery of siRNA both in vitro and in vivo, resulting in strong inhibition of the targeted gene. The company will refine the siRNA method in vitro using immortalized cells, evaluate various methods for effecting siRNA action in rodents and large mammals, and apply the optimized delivery methods in animal models to inhibit expression of genes involved in hypercholesterolemia, a much-studied condition of great interest to drug companies. The range of animal studies will help elucidate complicated biological pathways and enhance the utility of the results. Jefferson Medical College (Philadelphia, Pa.) will provide expertise in the hypercholesterolemia model. Mirus has achieved over 95 percent inhibition in vitro and in mice, but it is not known whether this rate will be achievable in primary cell cultures or in larger animals, or whether the liver can be targeted without affecting other organs. The company has been unable to find adequate private funding because of the high R&D risks at this early stage of the work. ATP support will accelerate the research by 2 to 3 years. If successfully developed and deployed, the new technology will greatly increase the speed and specificity of drug target validation, enabling industry to make better choices about which targets to develop and accelerating the development and reducing the costs of new drugs. In addition, siRNAs themselves could have therapeutic applications, such as in reducing the liver's production of the "bad" form of cholesterol or in combating the effects of biological weapons.

For project information:

David Lewis, (608) 441-2858
davel@genetransfer.com

ATP Project Manager

Douglas Bischoff, (301) 975-8597
douglas.bischoff@nist.gov