General Competition (March 1997)

Development of Novel DNA Binding Proteins as Antiviral Therapeutics

Sponsor: Sangamo BioSciences, Inc.

• Project Performance Period: 5/1/1997 - 4/30/2000
• Total project (est.): $2,680,000.00
• Requested ATP funds: $2,000,000.00

Viral diseases have long been among the toughest challenges for medical research. When compounds to cure or prevent viral diseases are discovered, these drugs are often highly disease-specific. There are no broad-spectrum anti-viral medications like antibiotics which are effective against bacterial infections. Researchers at Sangamo BioSciences suggest that recent developments in the understanding of proteins that bind to specific sites in DNA molecules offer the possibility of a novel strategy for designing antiviral drugs that function at the genetic level, using nature's own approach to gene regulation. Sangamo's approach is based on a class of DNA binding proteins called "zinc-fingers", which appear to bind DNA according to certain "recognition rules". In principle, zinc-finger proteins can be designed to recognize and bind to any gene or DNA sequence. Research has demonstrated that these binding proteins can repress or "turn off" the activity of a specific gene; the key to the Sangamo project. Sangamo proposes to develop the techniques necessary to design and build specific zinc-finger DNA binding proteins that suppress the activity of any clinically relevant gene required by target viruses. For example, the Human Immunodeficiency Virus (HIV) is believed to require the presence of a specific protein on the surface of immune cells in order to infect those cells. People who lack this protein because of a natural genetic mutation apparently are either immune or highly resistant to HIV. An engineered DNA binding protein that inhibits the production of this surface protein might convey similar resistance to HIV. In a direct anti-viral approach, the Hepatitis B Virus (HBV) is believed to be vulnerable to a DNA binding protein attack that would inhibit transcription of the virus's own DNA. Major challenges facing this project include increasing the specificity of the binding protein, from sequences of up to nine DNA base pairs to sequences of up to 15 to 18 base pairs. Sangamo proposes to pursue the development of highly specific DNA binding proteins for these viral diseases as part of their ATP project as well as to establish the basic methodologies for designing and building engineered zinc-finger proteins for any antiviral applications.

For project information:

Edward Lanphier, (510) 748-3036
elanphier@sangamo.com

ATP Project Manager

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