Claret Bioscience is developing a next-generation sequencing (NGS) library preparation technique that can be deployed as a liquid biopsy DNA assay. Liquid biopsy recovers biomarkers like DNA and other cellular material found circulating in the blood and other bodily fluids, called cell-free DNA (cfDNA). In individuals with tumors, a small portion of the overall cfDNA will derive from the cancerous cells, sharing somatic variants with the tumor itself. Liquid biopsy thus promises a non- invasive means of detecting and genotyping a patient's solid tumor. However, there are few cfDNA- based assays approved today for clinical diagnostic use. They are restricted to relatively few known cancer-driving variants, limiting the scope of cancer screening and the utility of high-throughput sequencers. Claret's solution is an NGS liquid biopsy assay that aims to broadly and agnostically identify DNA of abnormal origin. Our high-throughput assay exploits a novel cfDNA biomarker by recovering and charactering signals of DNA degradation found only at the termini of cfDNA fragments. The major potential outcome of our technology is a liquid biopsy tool that is additive, providing valuable cfDNA sequence data while simultaneously exploiting biologically degraded fragment ends - information lost to all NGS methods to date. The technical challenge of bringing our innovation to the NGS and/or liquid biopsy market hinges on two central challenges. First, the assay must efficiently convert a pool of cfDNA molecules into a sequencing library with high fidelity such that the actual DNA molecular ends are captured. Our first Phase I goal is thus assay optimization. We will measure fidelity, efficiency, reproducibility, sensitivity using a series of experimentally-designed synthetic controls. The second challenge is to discern the biological utility of the characterization of cfDNA termini. We designed our second aim of Phase I to probe for specific signals that may be indicative of disease state and assayable from cfDNA. We focus on matched sets (tissue diseased, tissue normal, blood plasma) of clinical samples from treatment-nave donors with known cancer types. The proposed Phase I proof-of-concept experiments and assay optimizations will yield a path to a commercially viable product capable of revealing important patterns of DNA degradation from healthy and diseased samples. Project Summary - 1

Public Health Relevance

Liquid biopsy recovers biomarkers like DNA and other cellular material found in the blood and other bodily fluids. In individuals with tumors, a small portion of the overall cell-free DNA (cfDNA) will derive from the cancerous cells. As such, new approaches to investigate cfDNA via liquid biopsy hold extreme promise for noninvasive biomedical discovery. This is especially true in oncology where the intractability of surgical tumor biopsies, serial or otherwise, hinders early detection, monitoring of treatment and tracking disease progression. Claret Bioscience has developed a next generation sequencing tool that exploits the unique signals of DNA breakdown for each individual cfDNA molecule in real time. The mission is to deploy this technology as a high-throughput liquid biopsy assay for clinical use in the evaluation of broad cancer detection and monitoring. ! Project Narrative - 1

National Institute of Health (NIH)
National Cancer Institute (NCI)
Small Business Innovation Research Grants (SBIR) - Phase I (R43)
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Special Emphasis Panel (ZRG1)
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Zhao, Ming
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Claret Bioscience, LLC
United States
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