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MOUNTAIN VIEW, CA, United States

Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 249.47K | Year: 2009

DESCRIPTION (provided by applicant): More than 15,000 allogeneic and 30,000 autologous hematopoietic stem cell transplantations (HSCT) are performed annually worldwide (1). Approximately 40% of patients that undergo allogeneic HSCT die from transplantation-related complications, in part due to toxicity of the conditioning regimen to non-hematopoietic tissues (1, 5). A recent approach to decrease conditioning regimen toxicity has been targeted radiotherapy, in which therapeutic doses of radiation are selectively delivered to bone marrow by use antibodies or compounds that indirectly target the bone matrix (5). Targeted radiotherapy can allow for therapy escalation to specific sites such as bone marrow, and provides treatment intensification without toxicity to non-hematological tissues (5). Marrow components can also be indirectly targeted using agents that naturally accumulate within bone re-mineralization sites. Despite advances made using these targeted radiotherapy conditioning regimens, problems still exist. An optimal combination of vector/target antigen and radioisotope has not been achieved, specific transplant protocols have not been determined, and use for the most appropriate diseases has not been pinpointed. To address these issues, we would like to explore a new avenue of myeloablative conditioning therapies that do not utilize radiation, but rather small molecular weight drugs. We propose to identify genes required for survival of only hematopoietic stem cells and committed progenitors, but are not critical for survival of other cell types, by use of RNAi library screening technology. Once identified, these gene products can be used as drug targets for the development of novel myeloablative therapies that will target only cells of the hematopoietic lineage. The rationale is that novel myeloablative therapies that target only those cells of the blood lineage, while leaving other cells of the body unaffected, will greatly reduce the toxicity of conditioning regimens and improve survival rates of patients who must undergo HSCT (5). Development of this technology will provide a publicly available prototype blood cell lineage database outlining reconstructed viability genes and associated pathways, and a set of human FV shRNA libraries, custom services, and RNAi screening technical support will be offered as commercial products and custom services to Cellecta's customers. PUBLIC HEALTH RELEVANCE: The goal of this project is to identify viability genes of hematopoietic stem and progenitor cells in order to find drug targets for new stem cell transplantation and blood cancer therapies. Genes will be identified using RNAi technology, and technology development will allow for production of gene databases, RNAi library products, and the refinement of custom services for our customers.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 237.37K | Year: 2009

DESCRIPTION (provided by applicant): The heat shock response (HSR) induced by cell stress is a common protection mechanism elicited in a wide range of tumors. This response is closely associated with a poor prognosis and resistance to therapy. Phase I of this proposed research aims to identify drug targets involved in the HSR. These potential drugs, which are expected to inhibit the HSR, may be used in combination with known activators of cell stress, such as heat shock, Bortezomib and Geldanamycin, for improved treatment of cancers. In addition, completion of Phase I of the proposed research will result in generation of a prototype database of HSR pathway regulation in a wide range of cell lines of diverse tumor origin. Phase II of this research proposes in-depth characterization of drug targets involved in the HSR/PTS pathway and development of the reporter cell lines for high throughput screening (HTS) of a chemical compound library. Given our unique interface with cellbased drug screening facilities available at Roswell Park Cancer Center, we expect to develop a pipeline of potential drugs with fast conversion of pathway knowledge into efficient strategies of drug identification. At completion of the proposed studies, we anticipate that we will have generated a novel class of anti-tumor drugs with no equivalent properties previously described in the literature or applied in clinical trials. We propose that these drugs be used in combination with drugs known to activate the HSR through inhibition of basal heat shock machinery, such as Bortezomib and Geldanamicin, or in combination with heat therapy. Our preliminary studies argue in favor of a very strong synergistic effect of these drugs in the induction of tumor cell death. PUBLIC HEALTH RELEVANCE: The goal of this project is to identify drug targets within the heat shock response pathway for establishment of novel approaches to discover anti-cancer therapies through isolation of chemical compounds blocking heat shock response in tumors. Drug targets will be identified through RNAi technology, allowing for development of RNAi library products and generation of databases of cell lines, genes, and molecular pathways.


Patent
Cellecta, Inc. | Date: 2014-01-13

Methods of obtaining a single cell expression profile from a target mammalian cell are provided. Aspects of the methods include contacting a cellular sample which includes the target mammalian cell with a packaged viral barcoded trans-splicing library including a plurality of barcoded trans-splicing constructs under transduction conditions, where a barcoded trans-splicing construct includes a trans-splicing element linked to a barcode element. The methods further include generating expression data from the resultant transduced target mammalian cell to obtain the single cell expression data from the target mammalian cell. Also provided are compositions, e.g., libraries and components thereof, which find use in practicing the methods.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 999.60K | Year: 2012

The DNA Damage and Repair (DDR) signaling modules are among the most commonly deregulated genes in human tumors. Deficiencies in DDR pathways are believed to influence tumorigenic processes by promoting a mutator phenotype, which contributes to the acquisition of genetic lesions and fuels malignant transformation. As DDR networks are extensively rewired in cancer cells, the concept of synthetic sickness/lethality (SL) can be exploited to identify novel therapeutic target(s) for cancer. RNA interference(RNAi) currently makes it possible to use high-throughput functional genomic strategies for SL target identification. Unfortunately, while RNAi has opened new avenues for improving the drug discovery process, these avenues remain only potential opportunities until we develop robust RNAi screening technologies, which include experimental and bioinformatics tools for drug target discovery, validation and integration into operational cell-based models. To address these issues, as outlined in the 290 SBIRcontract proposal, the development of a novel orthogonal functional genomics platform based on validated lentiviral shRNA libraries to facilitate the discovery of SL molecular targets en masse will be required. Accordingly, the ultimate goal of the 290SBIR research project is to develop and commercialize a human pooled SL shRNA library that targets all of the canonical and non-canonical DDR (400x400) gene combinations and to validate their application in RNAi screens in cancer cell models. This project will also require the development of supporting tools, including a public SL DDR database, protocols, reagents and software tools for in vitro screening, and the validation of the SL hits that specifically control the proliferation and survival of cancer cells. The aforementioned genetic screening and bioinformatic tools will provide the research community with highly modular and cost-effective approaches to understand and integrate dynamic changes in DDR signaling networks for the discovery of novelanti-cancer SL targets.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 199.68K | Year: 2010

Despite 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 application of this information for the development of novel drugs. RNA interference (RNAi) now makes it possible to use high-throughput functional genomic strategies for SL target identification. Unfortunately, while RNAi has opened new avenues for improving the drug discovery process, these avenues remain only potential opportunities until we develop robust RNAi screening technologies, including experimental and bioinformatics tools for data validation and integration into operational cell-based models. To address these issues and, as outlined in the 290 SBIR contract proposal, it will require to develop a novel orthogonal functional genomics platform based on validated lentiviral shRNA libraries to facilitate discovery of SL molecular targets en masse. Accordingly, the ultimate goal of the 290 topic research project is to develop and commercialize a set of human and mouse pooled SL shRNA libraries targeting all cannonical DDR gene combinations and validate their application for RNAi screens in cancer cell models. As a supporting tools, it will also require to develop protocols, reagents and software tools for in vitro and in vivo screening SL hit validation and therapeutic target prioritization that specifically control the proliferation and survival of cancer cells. The aforementioned genetic screening and bioinformatic tools will provide the research community with highly modular, cost-effective approaches to understand and integrate the dynamic changes in DDR signaling networks for the discovery of novel anti-cancer SL targets.

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