State the application's broad, long-term objectives and specific aims, making reference to the health relatedness of the project (i.e., relevance to the mission of the agency). Describe concisely the research design and methods for achieving these goals. Describe the rationale and techniques you will use to pursue these goals. In addition, in two or three sentences, describe in plain, lay language the relevance of this research to public health. If the application is funded, this description, as is, will become public information. Therefore, do not include proprietary/confidential information. Genome engineering is an emerging field in which targeted genome modifications are made for biotechnological and therapeutic applications. Site specific rare cutting endonucleases are a crucial tool for genome engineering, as they are required to create DNA double strand breaks at desired genomic sites. Endonuclease-induced double strand breaks are resolved by endogenous DNA repair pathways, resulting in high efficiency gene editing if resolved via non-homologous end joining, or targeted gene modification if resolved via homologous recombination. Precision Genome Engineering has developed proprietary methods for generation and isolation of rare cutting endonucleases based on the use of the I-AniI LAGLIDADG homing endonuclease as a scaffold. This phase I STTR will support the application of this approach to generate a novel LAGLIDADG nuclease capable of cleaving the human CCR5 gene. Such a nuclease can be applied for generation of CCR5- deficient T-cells. CCR5-deficient T-cells are resistant to infection by CCR5-tropic strains of HIV, the most common form of HIV in the United States. Generation of such T-cells and re-engraftment in an HIV infected patient represents a new approach to treatment of established HIV infections with significant promise.

Public Health Relevance

This project will support development of an engineered site specific nuclease capable of cleaving the human CCR5 gene. This protein or refined derivatives will be applicable to generation of CCR5-deficient T-cells, a novel approach to therapy of HIV infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Small Business Technology Transfer (STTR) Grants - Phase I (R41)
Project #
1R41GM085876-01A1
Application #
7747074
Study Section
Special Emphasis Panel (ZRG1-AARR-E (16))
Program Officer
Portnoy, Matthew
Project Start
2009-09-01
Project End
2011-02-28
Budget Start
2009-09-01
Budget End
2011-02-28
Support Year
1
Fiscal Year
2009
Total Cost
$101,156
Indirect Cost
Name
Precision Genome Engineering, Inc.
Department
Type
DUNS #
781229211
City
Seattle
State
WA
Country
United States
Zip Code
98103
Certo, Michael T; Gwiazda, Kamila S; Kuhar, Ryan et al. (2012) Coupling endonucleases with DNA end-processing enzymes to drive gene disruption. Nat Methods 9:973-5