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Redwood City, CA, United States

Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 1.60M | Year: 2009

DESCRIPTION (provided by applicant): In each IVF cycle, a decision must be made as to which embryo(s) will be selected for transfer. This decision has a far reaching impact on the outcome of an IVF cycle, namely whether the embryo will develop into a healthy child. It is estimated that at least 50% of human embryos are affected by chromosomal abnormalities such as aneuploidy, and implantation of such embryos can lead to undesired outcomes such as failed implantation, spontaneous abortion, or birth of a trisomic offspring. Reproductive specialists have been increasingly turning to pre-implantation genetic diagnosis (PGD) in efforts to identify embryos with the best chance of developing into healthy children. However, current techniques are expensive, unreliable and typically test only a small selection of chromosomes. GSN has developed an innovative technology termed Parental SupportTM (PS) whose output is an in silico reconstruction of the embryonic DNA at thousands of loci with confidence exceeding 99%. This technology will, for the first time, allow IVF physicians to screen embryos for chromosomal abnormalities including aneuploidy, translocations and deletions across all 23 pairs of chromosomes with an error rate below 0.1%. The Phase I objective of this application is to integrate our PS technology with a new, highly parallelized custom Infinium-based genotyping platform to dramatically reduce costs that will, in turn, enable GSN to offer PGD service with superior accuracy, scope and at a cost equivalent to current, less reliable FISH methods. The new customized platform will then be applied in Phase II where we propose to evaluate the concordance between a new trophectoderm biopsy technique on day 5, traditional blastomere biopsy on day 3, and the actual child. The results from these studies will allow us to assess the value of the new biopsy technique, evaluate the largely unstudied phenomenon of embryo self-correction between day 3 and day 5, and provide IVF physicians with powerful and far-reaching knowledge about the developmental potential of each embryo.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 200.83K | Year: 2010

DESCRIPTION (provided by applicant): During the course of a pregnancy, physicians and patients desire as much information as possible regarding the health of the fetus. For both emotional and medical reasons, this information is sought as early in term as possible, and with the fewest possible risks to both mother and child. Although the widely used first trimester chorionic villus sampling (CVS) and second trimester amniocentesis are relatively safe, both procedures are not without negligible risks. In efforts to avoid these risks altogether, researchers have turned toward isolating circulating fetal nucleated red blood cells (FNRBCs) from maternal blood as an alternative, non- invasive source of fetal tissue. Despite the development of FNRBC enrichment methods, there has been limited success with their coupling to subsequent aneuploidy screening and several challenges still must be overcome such as ability to test single fetal cells for 24-chromosome aneuploidy, confirm the isolated cell's origin (fetal versus maternal) and simultaneously screen for diseases caused by single nucleotide variants or micro in/dels. Our innovative Parental SupportTM technology provides a solution to all of these challenges and the development of a first trimester non-invasive prenatal diagnostic test is the ultimate goal of this grant application. In Phase I, we first plan to optimize single cell lysis and whole genome amplification protocols specifically for antibody-stained FNRBCs.. Protocol optimization for single cell analysis falls within the core competencies of GSN as we have previously successfully commercialized an innovative single cell molecular karyotyping protocol to enable genetic analysis of single blastomeres within 24 hours. We will then systematically evaluate which combination of existing FNRBC enrichment methods provides maximum yield and purity suitable for subsequent Parental Support -based genetic analysis using predefined mixtures of fetal and adult blood. The main objective of Phase II will be to transition from the predefined blood mixtures of fetal and adult blood to actual maternal blood samples. We will first conduct a pilot study to determine which of the best FNRBC isolation method(s) identified in Phase I should become the lead method. Using this lead method, we will then conduct a larger study to evaluate concordance between aneuploidy diagnosis by Parental SupportTM and karyotyping by amniocentesis or chorionic villus sampling. If successful, we expect that the completion of these Aims would have a major impact on the field of prenatal diagnosis, improve the lives of millions of couples and children worldwide, and bring non-invasive diagnosis to the mainstream of prenatal medicine. PUBLIC HEALTH RELEVANCE: In the absence of prenatal diagnosis, up to 1 in 50 babies have serious physical or mental handicaps, up to 1 in 30 babies have some form of congenital malformation, and up to 1 in 200 have a phenotypically significant chromosome abnormality Although these abnormalities can be diagnosed with techniques such as amniocentesis or chorionic villus sampling, both procedures carry an increased risk of harm to both the mother and fetus. Our innovative technology has the potential to evaluate the health of an unborn child by simply analyzing the mother's blood, thereby minimizing the risks of the procedure and expanding prenatal screening to the general population.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 1.60M | Year: 2011

DESCRIPTION (provided by applicant): During the course of a pregnancy, physicians and patients desire as much information as possible regarding the health of the fetus. For both emotional and medical reasons, this information is sought as early in term aspossible, and with the fewest possible risks to both mother and child. Although the widely used first trimester chorionic villus sampling (CVS) and second trimester amniocentesis are relatively safe, both procedures are not without negligible risks. In efforts to avoid these risks altogether, researchers have turned toward isolating circulating fetal nucleated red blood cells (FNRBCs) from maternal blood as an alternative, non- invasive source of fetal tissue. Despite the development of FNRBC enrichment methods, there has been limited success with their coupling to subsequent aneuploidy screening and several challenges still must be overcome such as ability to test single fetal cells for 24-chromosome aneuploidy, confirm the isolated cell's origin (fetal versus maternal) and simultaneously screen for diseases caused by single nucleotide variants or micro in/dels. Our innovative Parental SupportTM technology provides a solution to all of these challenges and the development of a first trimester non-invasiveprenatal diagnostic test is the ultimate goal of this grant application. In Phase I, we first plan to optimize single cell lysis and whole genome amplification protocols specifically for antibody-stained FNRBCs.. Protocol optimization for single cell analysis falls within the core competencies of GSN as we have previously successfully commercialized an innovative single cell molecular karyotyping protocol to enable genetic analysis of single blastomeres within 24 hours. We will then systematically evaluatewhich combination of existing FNRBC enrichment methods provides maximum yield and purity suitable for subsequent Parental Support -based genetic analysis using predefined mixtures of fetal and adult blood. The main objective of Phase II will be to transition from the predefined blood mixtures of fetal and adult blood to actual maternal blood samples. We will first conduct a pilot study to determine which of the best FNRBC isolation method(s) identified in Phase I should become the lead method. Using this lead method, we will then conduct a larger study to evaluate concordance between aneuploidy diagnosis by Parental SupportTM and karyotyping by amniocentesis or chorionic villus sampling. If successful, we expect that the completion of these Aims would have amajor impact on the field of prenatal diagnosis, improve the lives of millions of couples and children worldwide, and bring non-invasive diagnosis to the mainstream of prenatal medicine. PUBLIC HEALTH RELEVANCE: In the absence of prenatal diagnosis, up to 1 in 50 babies have serious physical or mental handicaps, up to 1 in 30 babies have some form of congenital malformation, and up to 1 in 200 have a phenotypically significant chromosome abnormality Although these abnormalities can be diagnosed withtechniques such as amniocentesis or chorionic villus sampling, both procedures carry an increased risk of harm to both the mother and fetus. Our innovative technology has the potential to evaluate the health of an unborn child by simply analyzing the mother's blood, thereby minimizing the risks of the procedure and expanding prenatal screening to the general population.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 1.49M | Year: 2008

DESCRIPTION (provided by applicant): In 2006, across the globe, more than 800,000 in-vitro fertilization (IVF) cycles were run. Of 150,000 cycles run in the US, roughly 10,000 involved pre-implantation genetic diagnosis (PGD). Current PGD techniques are un regulated, expensive and highly unreliable: error rates for screening disease-linked loci or aneuploidy are on the order of 10%; each screening test costs more than 5,000; and a couple is forced to choose between testing aneuploidy, which afflicts roughly 40% of IVF embryos, or screening for disease-linked loci on the single cell. There is a great need for an affordable technology that can reliably determine genetic data from the single cell in order to screen in parallel for aneuploidy, monogenic diseases such as Cystic Fibrosis, and susceptibility to complex disease phenotypes for which the multiple genetic markers are known through whole-genome association (WGA) studies. The process of PGD during IVF involves extracting a single cell from the roughly 8 c ells of an early-stage embryo for analysis. Since only a single copy of the DNA is available from one cell, direct measurements of the DNA are highly error-prone, or noisy. Gene Security Network (GSN) has developed a novel technology, termed Parental Suppo rtTM (PS), for determining the embryonic DNA at hundreds of loci together with copy numbers for 23 chromosomes, with error rates below 0.1%, from a single cell. The proprietary technique makes use of genetic data of the mother and the father, together with the knowledge of the mechanism of meiosis and noisy measurements of the embryonic DNA, in order to determine which segments of parent chromosomes contributed to the gametes that fertilized and hence to reconstruct in silico the embryonic DNA with confiden ce exceeding 99%. Based on the results of our phase I study, GSN has executed letters of intent with the 5 leading IVF centers in the United States to use the GSN diagnostic service. In aim 1 of this proposal, we will demonstrate the ability of the PS tech nology to reliably reconstruct genetic data using the measured genetic data from isolated single cells from a born child, and parental genetic data. In aim 2 we will demonstrate the ability of the PS technology to detect aneuploidy at all 23 chromosomes, a lso using isolated single cell genetic data, by means of an innovative single cell model for aneuploidy that does not require direct work on embryos. In Aim 3 we will perform a clinical trial in conjunction with Stanford IVF Center, Boston IVF and Huntingt on Reproductive Center that applies the techniques from aims 1 and 2 to real blastomeres in the IVF context and compare our predictions with truth measured on the child when born. One goal of the study is to generate data that will be used to obtain approv al of this diagnostic technique by the Food and Drug Administration. The PS technology of Gene Security Network will bring the domain of PGD into the realm of reliable diagnostics which can be regulated and used with confidence in clinical decisions. The s election of the embryos to implant is a clinical decision that has direct and absolute impact on outcomes. Narrative and Relevance to Healthcare PUBLIC HEALTH RELEVANCE: As data associating disease phenotypes with genotype continues to grow, the question arises: how can this knowledge be used to improve the quality of life and health? With this grant, Gene Security Network will thoroughly validate a technology for screening embryos during in-vitro fertilization for a multiplicity of disease linked genes an d TM aneuploidy. This technology, termed Parental Support (PS) which is built on the fundamental principles of meiosis and data that has recently become available through the human genome project. Compared to existing technologies, PS enables: i) determina tion of disease linked loci with roughly two orders of magnitude lower error rates; ii) determination of multiple disease-linked loci in parallel; iii) dete


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 195.75K | Year: 2007

DESCRIPTION (provided by applicant): In the process of pre-implantation genetic diagnoses (PGD), a single blastomere is removed from the early stage embryo for analysis. Currently, most PGD techniques focus on detection of chromosomal abnormalities such as aneuploidies and balanced translocations.1 However, in order to understand the inheritance of the majority of disease phenotypes, it will be necessary to measure multiple single nucleotide polymorphisms (SNPs) on the embryonic DNA. Techniques are available in research laboratories today, with estimated availability within two years, to measure SNPs from the DNA of a single cell. However, since only a single copy of the DNA is available from one cell, the SNP measurements will be highly error-prone or noisy. Gene Security Network has developed a proprietary technique, termed Parental Support TM, for cleaning the noisy measurements of embryonic DNA. In essence, the algorithm makes use of genetic data of the mother and the father, together with the knowledge of the mechanism of meiosis and the noisy measurements of the embryonic DNA, in order to reconstruct in-silicon the embryonic DNA at the location of key SNPS with a high degree of confidence. This project extends GSN's recent work in developing a translation engine for the efficient integration of multiple sets of pharamacogenomic data into a standardized ontology. The translation engine is used to create a cartridge for each local source of data. The cartridge translates the genetic, phenotypic and meta-data from the local source into the format of the standardized ontology, where it can be analyzed by expert rules and statistical models for data validation and outcome prediction. This work is being performed in collaboration with the PharmGKB Project at Stanford University. PharmGKB manages an openly-shared Internet repository for clinical trial data with the intent to uncover how individual genetic variation contributes to distinctive reactions to pharmaceuticals. As a member of the NIH Pharmacogenetics Research Network (PGRN), PharmGKB's database includes extensive pharmacokinetic and genomic records from cardiovascular, pulmonary, and cancer research. In aim 1, we will extend GSN's work with PharmGKB by working with pharmGKB to create a standardized, computable ontology for genotyping array data together with a cartridge for integrating Affymetrix genotyping array data into that format. This will enable PharmGKB to efficiently make high-throughput genotyping data publicly available for pharmacogenomic research. The computable genotyping data standard will also establish the foundation for aims 2 and 3 of this project. In aim 2, we will demonstrate the utility of the computable data format by inputting high-throughput genotyping array data from an Affymetrix 500k Gene chip Array into that standard and predicting the susceptibility to key disease phenotypes, based on data aggregated from the public domain. In aim 3, we will refine and implement the Parental Support TM technique for cleaning the embryonic DNA, measured using either PCR-based techniques, or molecular inversion-probe (MIPS) based techniques. Relevance to Healthcare Aim 1 provides a standardized ontology for genotyping array data, and a cartridge for easily submitting genotyping array data into the public domain. Having this data in the public domain will considerably benefit research in understanding gene-disease association and gene functions. In addition, the availability of the genotyping data in standardized computable format will ultimately enhance the ability of doctors to use that information for clinical decisions. Aim 2 will enable the knowledge of gene-disease associations to enhance pre-implantation genetic diagnosis. Aim 3 will refine the Parental Support method to enable genotyping technologies, operating on a single cell, to produce reliable genotyping data in the IVF setting. This reliable genotyping data is absolutely critical for the task of predicting susceptibilities to various disease phenotypes.

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