Tissue Collection for Disease Modeling
Induced pluripotent stem cells are stem cells that can be derived from a differentiated cell by introducing genes which, when over-expressed, revert the cell into a less differentiated state. These cells are very valuable because they can be programmed to differentiate once again into a variety of cell types. The purpose of this study is to provide blood cells from patients with congenital heart disease as well as from healthy controls for the generation of lines of induced pluripotent stem cells that can be used to unravel the molecular basis for specific congenital heart diseases. In many cases, the causes of the disease are not known or are multi-faceted and not well understood. The cells will provide a valuable research resource for scientists interested in identifying why specific congenital heart diseases occur. The cells will also be used to develop new ways to repair the heart. There are approximately 36,000 infants born each year with a congenital heart defect and congenital heart disease affects between one and two million adults in the United States. The availability of these cells will not only provide a valuable research resource but can also be used to develop safer drugs for young patients whose heart cells respond differently to drugs when compared with adults. This resource will provide the opportunity for new and better treatments to be made available for all patients with congenital heart disease.
Statement of Benefit to California:
The American Heart Association has reported that the costs of treating heart disease in the United States are expected to soar from $272.5 billion to $818 billion dollars over the next twenty years. Since heart disease is one of the most common chronic health conditions in California, the associated costs of treating these patients will be a significant public health challenge in this state. The current costs of annual health care for California residents with heart disease exceed $12,900 per capita, over five times the health care costs of the general adult population. It would benefit California, and the general population, if scientists could develop new and cost-efficient treatments for patients with heart disease. Our clinical and biomedical research team proposes to provide samples from patients with congenital heart disease to develop a research resource of induced pluripotent stem cells that can be used to study congenital heart defects that impact children and one to three million adults in this country. The development of stem-based therapies would be facilitated by this resource, thereby improving patient outcome and reducing medical care costs. New methods for the use of these cells, in partnership with industry, can bring new revenue to California.
This application describes collection of a tissue resource using blood drawn from an ethnically diverse population of pediatric patients suffering from a spectrum congenital heart defects (CHD). This resource will be used to develop iPSC lines that could subsequently be used for the development of CHD disease models. Ultimately, the applicant predicts these models will be useful to the scientific community in understanding the molecular basis of CHD disease processes and as surrogates for pediatric drug testing. Impact and Significance - The impact of the work could be constrained by a lack of focus upon a single disorder. For some CHD, only a few patients are represented, leaving reviewers uncertain of the collection’s ultimate utility. - Reviewers questioned the impact of the work, as they were unconvinced that CHDs are amenable to drug treatment or cell therapy. - CHD represent common birth defects, the causes of which are poorly understood. Further, while surgical interventions can enable survival, many patients continue to suffer complications of these disorders into adulthood. Rationale - The application did not address how one would recapitulate or assess the complex multicellular developmental biology of the heart in vitro, leaving the panel unclear how, or if, many CHD lesions could be modeled with iPSC lines. - The choice of CHD patients under study appeared to be driven by patient access at the host institution rather than by a clear scientific rationale. - The panel questioned the study of progenitors. Quality of the Proposed Protocols - Consent and sample availability appear appropriate. - It was unclear to reviewers how patient and control subject clinical data would be gathered and how this data would be linked to the samples Feasibility - Reviewers would have appreciated preliminary data that CHD lesions such as a valve or septal defects could be modeled in vitro. - While the applicant is experienced using patient samples under informed consent, historically observed intraoperative consent rates may not translate to this program. - The composition of the normal volunteer control population (age, wellness) was unclear. Budget - Overall the budget is modest and appropriate. - The source of pay for the research coordinator was unclear from the application. - The panel questioned the study of progenitors and the role of the individual isolating them presented in the budget justification. Qualifications of the Principal Investigator (PI) and Team Members, Resources - The PI has a strong and relevant funding and publication record as well as the expertise required to support the proposed study. - The assembled team possesses appropriate cardiac and surgical expertise; however, the group lacks a cardiac developmental biologist to inform patient and lesion selection for study.
- PROGRAMMATIC DISCUSSION
- - A motion was made to move this application to Tier 1 “Recommended for Funding”. The motion failed due to lack of a second.