Cellecta, Incorporated — Department of Health and Human Services SBIR Phase I: 172

Description

DESCRIPTION provided by applicant Despite of rapid advances in elucidating the molecular basis of human diseases an ostensibly more difficult post genomic challenge is the functional annotation of disease specific signaling pathways and the integration of this information into the development of novel drugs Recent studies demonstrate that CRISPR CAS gene knock out technology can be used as a powerful tool for large scale functional genomic analysis in mammalian cells Unfortunately although the CRISPR CAS system has opened many potential avenues for improving the drug discovery process these avenues remain only potential opportunities until we develop robust commercially available CRISPR CAS screening technologies as well as experimental and bioinformatics tools for data validation and integration of this information into operational cell based models The ultimate goal of the proposed project is to develop a novel free public resource lentiviral sgRNA screening platform enabling scientists to perform genome wide CRISPR CAS genetic screens in a pooled format Specifically we propose using Phase I studies to prioritize the genetic screening performance of different sgRNA designs and to employ the best validated design to develop a K human sgRNA library targeting human genes Furthermore we will scale up the development and commercialization of a comprehensive set of human and mouse genome wide sgRNA libraries in Phase II studies These libraries will have improved performance and be designed for cost effective pooled format screening and identification of effectors by high throughput HT sequencing As supporting tools we will develop protocols reagents and software tools for screening data analysis and validation To test the performance of our functional genomics platform we propose to validate and compare our novel sgRNA and previously established shRNA resource to delineate the processes that underlie tumorigenesis in a panel of PDX derived lung cancer cell lines These newly developed sgRNA screening validation and software tools will be freely available for academic researchers through the open resource www decipherproject net site which was previously funded by NIH and developed by Cellecta for distributing genome wide shRNA libraries CRISPR CAS screening products and custom services will provide the research community with highly modular cost effective approaches for studies aimed at understanding and integrating dynamic changes in signal transduction networks and ultimately delineating disease specific phenotypes The proposed sgRNA screening and bioinformatics strategies harbor considerable potential to systematically identify new targets for therapeutic intervention and to facilitate the development of highly specific drugs biomarkers and novel therapeutic concepts PUBLIC HEALTH RELEVANCE Open Resource CRISPR CAS Genome Wide sgRNA Library Screening Platform The ultimate goal of the proposed project is to develop a novel free public resource lentiviral sgRNA screening platform enabling scientists to perform genome wide CRISPR CAS genetic screens in mammalian cells Through specific and irreversible inactivation one gene at the time in a pooled cell population of each protein encoding gene in the human genome researchers will be able to associate specific gene inactivation to specific phenotypes such as disease progression or regression greatly facilitating the discovery of new therapy targets We believe this new screening platform will provide a powerful tool for improving the drug discovery process Gene specificity in CRISPR CAS technology is achieved by small molecules called sgRNAs which can be designed to recognize any DNA sequence The two main goals of the proposed phase I project are to optimize the technology through a prioritization screen aimed at selecting the sgRNA design performing best in genetic screens to employ the best validated design to develop a sgRNA library targeting human genes In Phase we will scale up the development and commercialization of a comprehensive set of human and mouse sgRNA libraries to cover the whole protein encoding genome As supporting tools we will develop protocols reagents and software tools for screening data analysis and validation These developed sgRNA screening validation and software tools will be freely available for academic researchers through the open resource www decipherproject net site which was previously funded by NIH and developed by Cellecta for distributing genome wide shRNA libraries CRISPR CAS screening products and custom services will provide the research community with highly modular cost effective approaches for studies aimed at understanding and integrating dynamic changes in signal transduction networks and ultimately delineating disease specific phenotypes The proposed sgRNA screening and bioinformatics strategies harbor considerable potential to systematically identify new targets for therapeutic intervention and to facilitate the development of highly specific drugs biomarkers and novel therapeutic concepts