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LOS ANGELES, CA, United States

Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 150.00K | Year: 2015

DESCRIPTION provided by applicant Systemic lupus erythematosus SLE is a systemic autoimmune disease with worldwide distribution Despite medical treatment morbidity and mortality from renal disease are still common in lupus patients However early diagnosis and prompt treatment can significantly improve long term prognosis Anti double stranded ds DNA autoantibodies are a serologic hallmark of patients with SLE In addition circulating microRNAs miRNAs have been shown recently to be systematically altered unveiling miRNA signatures with diagnostic utility Growing evidence suggests that a multi marker strategy containing a combination of biomarkers with high clinical sensitivity and specificity may enhance diagnostic and prognostic accuracy in the future compared to single marker tests To support efforts of identifying the most informative biomarker panels reliable next generation platform technologies are needed that permit multiplexed detection of both protein and nucleic acid targets in small samples and are suitable for automation and integration into the clinical laboratory work flow Nesher Technologies Inc NTI has exclusively licensed the intellectual property for an ultrasensitive and specific biodetection technology developed at the UCLA Single Molecule Biophysics Lab headed by Prof Shimon Weiss with high single well multiplexing potential minimal sample requirements and simplified handling procedures no separation washing and amplification steps It is based on alternating laser excitation ALEX single molecule fluorescence spectroscopy whereby target recognition molecules are tagged with different color fluorescent dyes and quenchers NTI recently achieved extension from color to color ALEX substantially expanding its multiplexing power and demonstrated diagnostic utility for direct protein as well as miRNA quantification Furthermore recent work by Profs Steve Quake and Shimon Weiss shows i combination of microfluidics based sample handling with ALEX spectroscopy termed andquot single molecule optofluidicsandquot and ii enhanced throughput using a multi foci excitation detection geometry NTIandapos s long term goal is to develop rapid highly multiplexed ultrasensitive and specific as well as fully automated nucleic acid and protein based diagnostic tests that require minimal sample sizes Here we propose assay development and clinical validation of a next generation test with significantly improved diagnostic prognostic and treatment guiding properties implementing a panel of autoantibody and miRNA biomarkers and overcoming limitations of current SLE testing Our Specific Aims are Initial reagent development for a multiplex miRNA andamp autoantibody based next generation test for SLE Separate as well as multiplexed biomarker detection and quantification using spiked samples ALEX based analysis of archived clinical samples and cross validation to ELISA and qPCR methods SBIR Phase II will propose assay expansion to include more markers miniaturization and development of a user friendly andquot sample in answer outandquot diagnostic system offering significant cost and patient sample savings PUBLIC HEALTH RELEVANCE Systemic lupus erythematosus SLE an autoimmune disease with an unpredictable course involving flares and remissions adversely affecting organ functions remains associated with an appreciably shortened life span As current single marker tests for SLE are inadequate there will be a great need for a versatile next generation platform technology to detect and quantify panels of diagnostic and prognostic protein and nucleic acid biomarkers as they become available in order to better assist in establishing early diagnosis of SLE refine prognosis guide management target treatment and finally improve patient survival Based on patent protected alternating laser excitation ALEX single molecule fluorescence spectroscopy Nesher Technologies Inc intends to make its single molecule detection SMD platform technology robust and easy to use for diagnostic labs as well as the broad research community and proposes to develop a next generation test for SLE monitoring a panel of microRNA and autoantibody biomarkers present in very small patient samples thereby translating cutting edge innovations in nanobiotechnology into benefits for the society at large by saving human lives and reducing healthcare costs


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 598.11K | Year: 2009

DESCRIPTION (provided by applicant): There is an urgent need for rapid, highly sensitive, specific, easy to use, and cost-effective medical diagnostic tests to diagnose individuals exposed to and/or infected with healthcare-associated pathogens that are pre-symptomatic, symptomatic, or have non-specific symptoms, and to accurately identify infectious agents or toxins in clinical samples so appropriate therapeutic intervention can be executed. As antibiotic resistance is spreading rapidly throughout the world causing growing costs in terms of human lives and healthcare expenditures, concomitant determination of increasingly complex microbial resistance patterns is of critical importance. However, as patient samples are limited and pathogen concentrations often extremely low (lt10 organisms/ml), serial analysis is not practical, thus requiring highly multiplexed systems instead of individual pathogen-specific tests. Nesher Technologies, Inc.'s (NTI) long-term goal is to develop a rapid, highly multiplexed (with a capacity of gt100 analytes per standard patient sample), ultrasensitive and -specific, quantitative, cost-effective, and fully automated, nucleic acid- and protein-based diagnostic system for bacterial infections, to allow quick and accurate pathogen identification in clinical samples, including acquired genetic traits such as antibiotic resistance or enhanced virulence. NTI has licensed the intellectual property for a revolutionary ultrasensitive biodetection technology with exquisite single well multiplexing potential, which was developed at the UCLA Single Molecule Biophysics Lab (headed by Prof. Shimon Weiss). It is based on 3- color alternating laser excitation (3c-ALEX) single molecule fluorescence spectroscopy, whereby two (or three) recognition molecules are tagged with different color fluorescence dyes. Coincident confocal detection of two or three colors constitutes a positive target detection event, allowing molecular identification of freely diffusing molecules in solution and detection of numerous targets simultaneously. Over the Phase I funding period, we will demonstrate feasibility by developing a test to simultaneously distinguish between 11 bacterial strains which are major pathogens responsible for nosocomial and community-acquired infections. Specific aims are: 1. Separate detection and quantification of eight genetic markers (species-specific for Staphylococcus aureus, S. epidermidis, Enterococcus faecalis, E. faecium, and Shewanella oneidensis as positive control; resistance-specific for methicillin, vancomycin A, and vancomycin B) in purified DNA derived from MSSA, MRSA, VRSA, MSSE, MRSE, VSEfaecalis, vanA VREfaecalis, vanB VREfaecalis, VSEfaecium, vanA VREfaecium, vanB VREfaecium, and S. oneidensis by 3-color ALEX-based fluorescence spectroscopy. 2. Multiplexed (single-well) discrimination and quantification of bacteria spiked into human blood. 3. ALEX-based analysis of 350 archived clinical isolates from UCLA's Medical Center (including 25 positive for each of the 11 pathogen types, except for rare VRSA) and statistical analysis. PUBLIC HEALTH RELEVANCE: Nesher Technologies, Inc.'s proposed development of a highly multiplexed, ultrasensitive, quantitative, low- cost automated medical diagnostic test system, capable of quickly identifying specific healthcare-associated bacterial strains and drug resistance patterns among the multitude of possibilities from a single patient sample, radically pushes the limits of current technologies. The improved diagnostic information will enable physicians to better prescribe the appropriate antibiotics to patients and enable hospitals to implement infection control procedures to lower their infection rates, thereby saving human lives and reducing healthcare costs. This will allow limiting the use of broad-spectrum antibiotics, encourage the development of narrowly targeted therapeutics, and help curtailing the marked global trend towards increasing antibiotic drug resistance which is a major concern for treatment and management of infectious diseases, affecting the health of millions of people in the United States and around the world.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 190.40K | Year: 2009

DESCRIPTION (provided by applicant): Single-molecule fluorescence resonance energy transfer (smFRET) has rapidly developed to answer fundamental questions about biological mechanisms, providing detailed views of molecular machines at work. Nesher Technologies, Inc. (NTI) was established to commercialize an innovative quantitative, ultrasensitive and -specific single-molecule biodetection technology with exquisite multiplexing potential and simplified sample handling procedures. It was pioneered at the UCLA Single Molecule Biophysics Lab, which is headed by Prof. Shimon Weiss. The technology is based on alternating-laser excitation (ALEX) of single molecules labeled with fluorescent probes. In addition to its suitability for diagnostics, ALEX has been employed recently to study the dynamics of molecular processes such as transcription initiation and elongation using smFRET. In two-color (2c)-ALEX, employing two alternating lasers to study molecular interactions (through probe stoichiometry ratio S and/or FRET efficiency E) and intramolecular distances for analysis of conformation and mechanism (through E), molecules are sorted in a two-dimensional histogram of S and E. In 3c-ALEX, molecules are sorted in three-dimensional S and E histograms, substantially extending the capabilities of 2c- ALEX. ALEX can be performed with diffusing molecules, enabling analysis of equilibrium behaviors of single molecules, or with immobilized molecules using millisecond-scale ALEX dynamic imaging (ALEX-DI). The ALEX-DI methodology, employing total-internal-reflection optical microscopy, has the advantage over its sister methodology, confocal microsecond-scale ALEX spectroscopy, that non-equilibrium time trajectories can be established to follow kinetics of individual molecules and complexes. Detailed stochastic molecule information on complex composition and function can be obtained as well. The ability to monitor individual molecules for long stretches of time adds a whole new dimension with dynamic information ranging from milliseconds to minutes. Higher-order FRET schemes can also be applied to probe transient multi-component interactions or spatiotemporal relationships between different conformational changes in large molecular complexes. NTI's long-term goal is development of a fully integrated 5-color ALEX-based instrument suitable for transient molecular complex characterization. The high-resolution power to monitor molecular interactions and conformational dynamics will also greatly aid structure-guided rational drug design endeavors. For Phase I, we propose to extend 2-color ALEX-DI to enable 3-color and 4-color functionality. Specific aims are: 1. Construction of an instrument for single-molecule total-internal-reflection optical microscopy with 4-color alternating-laser-excitation and dynamic imaging (4c-ALEX-DI). 2. Preparation of fluorophore-labeled bacterial transcription initiation complex components. 3. Use of 4c-ALEX-DI in 3-color and 4-color mode to detect and characterize DNA-scrunching in immobilized RNA polymerase (RNAP)-promoter initial transcribing complexes (RPitc), as well as promoter escape. PUBLIC HEALTH RELEVANCE: The proposed multi-color alternating-laser excitation (ALEX)-based single-molecule method for identifying and characterizing transient molecular complexes will vastly improve the ability to gather molecular information, which in turn will enhance our ability to understand the complex effects that subtle mutations and/or environmental factors have in the development and progression of diseases. The ALEX technology, highly useful for basic research as well as drug development applications, can complement structural analysis of biomolecules and their complexes, especially for species intractable by conventional structural biology methods due to excessive heterogeneity, limited stability, large size, presence of flexible domains, and/or transient nature. As an example, the proposed instrumentation will be able to facilitate detailed mechanistic studies of the bacterial transcription process, allowing rapid development of next-generation antibiotics (e.g. inhibitors of bacterial transcription at new sites of the transcription machinery), which is of critical importance for effective control of globally emerging multi-drug resistant bacterial strains, such as multidrug-resistant tuberculosis (MDR TB), extensively drug-resistant tuberculosis (XDR TB), methicillin-resistant Staphylococcus aureus (MRSA),and vancomycin-resistant enterococci (VRE).


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 150.00K | Year: 2015

DESCRIPTION provided by applicant Diabetes is a major cause of morbidity and mortality in the U S Given that the diabetes epidemic continues to grow worldwide there is a clear need for improvements in the management of the disease and its complications Early diagnosis and intervention can significantly improve long term prognosis Autoantibodies against islet antigens are a serologic hallmark of patients with Type Diabetes T D In addition circulating microRNAs miRNAs have been shown recently to be systematically altered indicative of miRNA signatures with diagnostic utility Growing evidence suggests that a multi marker strategy containing a combination of biomarkers with high clinical sensitivity and specificity may enhance diagnostic and prognostic accuracy in the future compared to single marker tests To support efforts of identifying the most informative biomarker panels reliable next generation platform technologies are needed that permit multiplexed detection of markers in small samples and are suitable for automation and integration into the clinical laboratory work flow Nesher Technologies Inc NTI has exclusively licensed the intellectual property for an ultrasensitive and specific biodetection technology developed at the UCLA Single Molecule Biophysics Lab headed by Prof Shimon Weiss with high single well multiplexing potential minimal sample requirements and simplified handling procedures no separation washing and amplification steps It is based on alternating laser excitation ALEX single molecule fluorescence spectroscopy whereby target recognition molecules are tagged with different color fluorescent dyes and quenchers NTI recently achieved extension from color to color ALEX substantially expanding its multiplexing power and demonstrated diagnostic utility for direct protein as well as miRNA quantification Furthermore recent work by Profs Steve Quake and Shimon Weiss shows i combination of microfluidics based sample handling with ALEX spectroscopy termed andquot single molecule optofluidicsandquot and ii enhanced throughput using a multifoci excitation detection geometry NTIandapos s long term goal is to develop rapid highly multiplexed ultrasensitive and specific as well as fully automated nucleic acid and protein based diagnostic tests that require minimal sample sizes Here we propose assay development and clinical validation of a next generation test with significantly improved diagnostic prognostic and treatment guiding properties implementing a panel of autoantibody and miRNA biomarkers and overcoming limitations of current T D testing Our Specific Aims are Initial reagent development for a multiplex autoantibody and miRNA based next generation test for T D Separate as well as multiplexed biomarker detection and quantification using spiked samples ALEX based analysis of archived clinical samples and cross validation to ELISA and qPCR methods SBIR Phase II will propose assay expansion to include more markers miniaturization and development of a user friendly andquot sample in answer outandquot diagnostic system offering significant cost and patient sample savings PUBLIC HEALTH RELEVANCE Type Diabetes characterized by a prolonged and variable latent period that culminates in the destruction of pancreatic beta cells and the development of hyperglycemia is a debilitating autoimmune disease and without proper management patients develop serious complications that reduce their quality of life and life expectancy As current single marker tests for T D are inadequate there will be a great need for a versatile next generation platform technology to detect and quantify panels of diagnostic and prognostic protein and nucleic acid biomarkers as they become available in order to better assist in establishing early diagnosis of T D refine prognosis guide management target treatment and finally improve patient outcome Based on patent protected alternating laser excitation ALEX single molecule fluorescence spectroscopy Nesher Technologies Inc intends to make its single molecule detection SMD platform technology robust and easy to use for diagnostic labs as well as the broad research community and proposes to develop a next generation test for T D monitoring a panel of autoantibody and microRNA biomarkers present in very small patient samples thereby translating cutting edge innovations in nanobiotechnology into benefits for the society at large by saving human lives and reducing healthcare costs


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 462.69K | Year: 2013

DESCRIPTION: To maximize clinical information content obtainable from a single small patient sample (e.g. cerebrospinal fluid-CSF), single molecule detection (SMD) technologies are the most promising for development of next- generation medical diagnostics. Recently, microRNAs (miRNAs) have been implicated in human malignancies including neurodegenerative disorders, offering the exciting prospect to combine traditional protein markers with novel miRNA candidate markers in panels. But as patient samples arelimited and marker concentrations often very low, serial analysis is not practical. Thus, only very sensitive methodologies with high multiplexing power will be able to maximize diagnostic value and be suitable for improved tests for early disease detection. Nesher Technologies, Inc. (NTI) has exclusively licensed the intellectual property for a revolutionary, quantitative, ultrasensitive and -specific biodetection technology, developed at the UCLA Single Molecule Biophysics Lab (headed by Prof. Shimon Weiss), with exquisite single-well multiplexing potential, minimal sample requirements, and extremely simplified workflows (no separation/washing and amplification steps). It is based on alternating laser excitation (ALEX) single molecule fluorescence spectroscopy, whereby target recognition molecules are tagged with different color fluorescent dyes (and quenchers), allowing, on the same platform, ultrasensitive detection of both proteins and nucleic acids (including miRNAs) in body fluids. NTI recently achieved extension from 2-color (2c) to 4-color (4c) ALEX, substantially expanding its multiplexing power (particularly when involving FRET), and demonstrated diagnostic utility for ultrasensitive protein as well as miRNA quantification at clinically relevantconcentrations without amplification. Furthermore, recent work by our consultants Profs. Steve Quake and Shimon Weiss shows i) combination of microfluidics- based sample handling with ALEX spectroscopy, a new breakthrough approach for assay miniaturizationtermed single molecule opt fluidics , and ii) enhanced throughput using a multifocal excitation/detection geometry. NTI's long-term goal is to develop rapid, highly multiplexed (with a capacity of gt100 analytes per sample), ultrasensitive and -specific,quantitative, cost-effective, and fully automated, protein- and nucleic acid- based diagnostic tests that require minimal sample sizes. Here we propose assay development and clinical validation for improved early-stage Alzheimer's disease (AD) diagnosis,implementing a panel of candidate protein and miRNA biomarkers. Our Specific Aims are: 1. Reagent development for a multiplex protein and microRNA biomarker-based next-generation AD test 2. Separate as well as multiplexed biomarker detection and quantification using spiked samples 3. ALEX-based analysis of archived clinical samples from 108 patients (PRoBE study design implementation) SBIR Phase II will propose assay expansion, miniaturization, and development of a versatile, user-friendly, diagnostic system as useful tool for early detection of AD and other neurodegenerative disorders. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: Early detection of neurodegenerative diseases including Alzheimer's disease is crucial for early intervention and to ensure optimal care and implementation of patient management strategies that may support improved quality of life. As disease-modifying treatments are being developed, there will be a great need for versatile next-generation platform technologies todetect and quantify panels of diagnostic and prognostic biomarkers as they become available to decide who should enter particular clinical trials, for determining who should or should not receive a particular therapy, for determining the likelihood of disease progression, and for tracking disease progression. Based on patent-protected alternating laser excitation (ALEX) single molecule fluorescence spectroscopy, Nesher Technologies, Inc. intends to make its single molecule detection (SMD) platform technology robust and easy to use for diagnostic labs as well as the broad research community, and proposes to develop a next-generation test for early detection of Alzheimer's disease, monitoring a panel of protein and microRNA biomarkers present in very small patient samples, thereby translating cutting-edge innovations in Nano biotechnology into benefits for the society at large by saving human lives and reducing healthcare costs.

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