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RL1-00668-1: Derivation of Novel Late Onset Disease-Specific Stem Cell Lines Using Highly Accurate Single Cell Genotyping Technology

Recommendation: Not recommended for funding

Public Abstract (provided by applicant)

The creation, propagation, and free distribution of novel human embryonic stem cell (hESC) lines are urgently needed in order to bring medical researchers one step closer to successfully treating many of the existing debilitating diseases. Although several federally approved embryonic stem cell lines exist, they are limited in their utility for a variety of reasons, most notably lack of genetic diversity. In order to fill this gap, we propose to derive novel hESC lines from embryos with inherited susceptibility to diseases that are relatively common and debilitating, such as cardiomyopathy, type II diabetes, early onset Alzheimer’s disease, and familial early onset breast cancer. Preimplantation genetic diagnosis (PGD) of embryos during in vitro fertilization (IVF) remains the most effective method for derivation of disease-specific hESC lines, and is the focus of this application.

A major drawback of current PGD methods is their inability to simultaneously detect both aneuploidy (a change in the number of chromosomes) and multiple genes known to cause a disease. Most PGD screens for embryos with abnormal number of chromosomes to improve implantation rates and reduce spontaneous abortions, and in nearly all other cases, PGD only screens for diseases that develop during early childhood. As a result, none of the PGD screens for diseases that develop during adulthood. We will be able to create that opportunity with our {REDACTED} product, which is the only method that can simultaenously measure both disease-linked genes and aneuploidy in a single cell isolated from an embryo.

In collaboration with our key California IVF clinic partners, we plan to first test our PSTM technology with unused embryos, and then apply the technology to screen hundreds to thousands of embryos per year. Given our ability to test for both chromosome abnormalities and genetic disease simultaneously, we will be in a unique position to screen each of these embryos for diseases that are not routinely tested by other PGD methods. With the parents’ consent, embryos that test positive for susceptibility to diseases of interest will be used to derive hESC lines and made available for free distribution to the research community worldwide.

If funded, we will derive hESC lines that will make several critical contributions to the field of stem cell research, ranging from empowering scientists to answer fundamental biological questions to facilitating the development of safe targeted therapeutics.

Statement of Benefit to California (provided by applicant)

Our company is headquartered in {REDACTED}. We provide technical, high-salaried employment for dozens of California residents. With Series A venture backing from {REDACTED} we have outlined an ambitious plan for growth, promising to bring even more jobs to the state. Additionally, we have close strategic partnerships with three California-based IVF clinics: {REDACTED} These IVF clinics, and their patients, will be among the first beneficiaries of our groundbreaking technologies. Most importantly, if this grant is funded, our company will, in collaboration with the {REDACTED} Department of Genetics, help bring novel human embryonic stem cell lines to California scientists. These disease-specific lines will be a superb resource for California researchers working to understand, prevent, and cure debilitating genetic diseases. This resource will help keep California at the forefront of stem cell research worldwide, enriching our local economy and earning further prestige for nonprofit research institutions. Local drug companies will benefit from local resources in nonprofit stem cell research. Finally, California residents could eventually benefit from advances in medicine that result from this important local biological resource.

Review

The applicant proposes to validate their proprietary and novel technology for Pre-implantation Genetic Diagnosis (PGD). The technology is designed to assess genetic information at a large number of disease-linked loci and to simultaneously measure chromosome copy number across all 24 chromosomes using single blastomeres extracted from human embryos. The applicant will also use embryos identified using this technology to generate human embryonic stem cell (hESC) lines carrying genetic risk factors for cardiomyopathy, familial early onset breast cancer, familial early onset Alzheimer’s disease and type 2 diabetes mellitus.

The establishment of hESC bearing particular genetic risk variants is highly important as the availability of reliable human cell-based models for the diseases targeted in this application would provide valuable research tools and might even lead to new therapies.

The applicant proposes to validate their pre-implantation genetic assessment technology. If this relatively untested technique were to work it would provide a leap forward in PGD. However, reviewers felt the method is unnecessary to discriminate affected embryos for the four diseases identified as targets for cell line derivation. These diseases would perhaps be better and more readily identified via traditional PGD approaches as they are all associated with very specific mutations. By relying on an un-validated PGD technique the overall feasibility of this proposal is therefore questionable. Furthermore, reviewers criticized that no independent quality assurance of the proprietary technology is presented or available, either through publication or through independent review by a third party, and critical experimental detail was lacking as well. This part of the proposal is thus hard to evaluate. For instance, a detailed description of the algorithm that enables the genetic assessment as proposed is minimally necessary if no independently evaluated data as to its effectiveness is to be presented.

Reviewers noted that the principal investigator is highly entrepreneurial and has assembled an impressive network of collaborators, including an expert in hESC derivation. Concern was expressed that certain milestones described in the supporting material so far have not been met.

The following Working Group members had a conflict of interest with this application and were therefore recused from participating in review of, discussion of, and voting on the application:

• None