Collection of tissue samples for the study of cardiac hypertrophy and simultaneous functional profiling of the diseased hearts to allow later validation of iPSC-derived in vitro models
Tissue Collection for Disease Modeling
Cardiac hypertrophy is a common manifestation of cardiovascular disease which results in the thickening of the cardiac wall reducing the ability of the heart to contract and efficiently pump blood throughout the body. The disease frequently results in heart failure and death. Most of our understanding of cardiac hypertrophy is derived from animal models that do not faithfully replicate the human disease. Cardiac hypertrophy is the results of complex interactions between genetic, epigenetic and metabolic factors. Current therapies have provided only limited benefit and there is tremendous need to understand this pathology in the hearts of patients with hypertrophy so that more effective therapies can be developed. The derivation of pathological cells and tissues through the in vitro differentiation of iPSC is a very promising approach. A key challenge remains the validation of the iPSC-derived cells with evidence that they are truly equivalent to the patient's tissue and constitute a useful model for experimenting new therapies. [REDACTED] specializes in the recovery of non-transplantable human hearts from organ donors and routinely tests the activity of new drug candidates on human hearts. Collecting samples from organ donors with or without cardiac hypertrophy, [REDACTED] will provide fibroblasts and cardiac progenitor cells for iPSC derivation. In addition the donors' hearts will be tested to generate data that will constitute a valuable reference for researchers.
Statement of Benefit to California:
California will benefit from this project in three ways: new and more effective therapies to treat heart failure, increased access to advanced research tools for California institutions and now jobs to the State in the fields of cardiovascular research and drug discovery. Heart disease and stroke are the number one and number three causes of death respectively, and a leading cause of disability, among Californians. Compared to the rest of the States in the Nation, California has slightly above average rates for coronary heart disease and stroke mortality. The establishment of a California-based repository of human iPSC derived from patients with cardiac disease and with an associated database of cellular physiological will create an unparalleled tool for the advancement of understanding of cardiac disease. The new knowledge will translate into increased intellectual property for the participating institutions in California. Furthermore a better understanding of the pathology will uncover novel potential therapeutic targets and stimulated efforts in drug discovery for the treatment of heart failure. These efforts will likely result in new high-tech drug discovery jobs.
The proposal focuses on the collection of cells from organ donors with Left Ventricular Hypertrophy (LVH), which will be used by the Deriver to generate human induced pluripotent stem cells (hiPSC). LVH is a multifaceted and variable disease that is thought to be genetically complex; risk factors include hypertension, diabetes, obesity, environmental factors, race and age. Currently, there are few appropriate preclinical models of the disease. The applicants propose to collect skin fibroblasts and cardiac progenitor cells from the heart during organ collection from consented organ donors who have a heart that is not suitable for transplantation. The heart function will also be measured and characterized in vitro to provide clinical and diagnostic data to be associated with the derived hiPSC lines. Samples will be obtained from 60 donors classified as having LVH and from 60 control donors. Derivation of hiPSC from these tissues, with subsequent differentiation into cardiomyocytes, could allow investigations of LVH disease etiology and pathology. Impact and Significance - LVH contributes significantly to the risk of cardiovascular disease and there is limited understanding of the triggers that lead to the disease. It has a complex etiology with high prevalence and is associated with significant rates of morbidity and mortality, which supports the goals of the RFA. - If cardiomyocytes differentiated from hiPSC that were derived from patients with LVH reflect the disease phenotype, this would provide a valuable resource for a field in which there are few preclinical models and considerable unmet need. Rationale - Reviewers questioned whether the proposed methods for classifying donor hearts as “hypertrophic” after organ collection were clinically relevant and widely established. Without characterization on the basis of a clear, well-accepted definition of the disease, the hiPSC lines that would be derived were predicted to be of limited value. - The proposal does not address anatomical and physiological changes in heart tissue that occur after brain death and organ collection; while not due to the underlying disease, these artifacts could confound postmortem assessment of the disease phenotype. - The proposal does not address selection of donors with particular LVH risk factors such as race. The small sample size proposed will yield a highly heterogeneous population that will dilute the phenotypic information available from the collection. - Protocols have been published that describe differentiation of immature cardiac cells from hiPSC and reviewers expressed confidence that the proposed contributions could be a source for successful differentiation of hiPSC-derived, immature cardiomyocytes. It is not clear, however, that immature cardiomyocytes differentiated from hiPSC would model the disease phenotype of an aged patient population. Quality of the Proposed Protocols - Some reviewers viewed the intention to functionally characterize the donor hearts and collect a data set for use by subsequent investigators as a strength of the protocol. - The applicants are experienced in organ and tissue procurement and have adequate protocols already in place for tissue preservation, characterization and data management. Feasibility - The applicant has an established track record for procuring donor hearts and performing the types of organ characterization studies described in the protocol. - The proposal was viewed as feasible, with the applicants providing details about recruitment strategies, infrastructure, sample tracking and logistics that support completion of the proposed work in the allotted time. - It was suggested that an ethicist evaluate the proposal to review whether consent for organ donation would be sufficient for the collections, derivation, sharing and commercial uses associated with this application. Budget - The budget was viewed as well presented and appropriate for the work proposed. - Although the budget is higher than those in some other proposals, whole organ collection and characterization is more costly than typical tissue sampling. Reviewers differed in their judgment of whether this cost is justified for this initiative. Qualifications of the Principal Investigator (PI) and Team Members, Resources - The PI’s demonstrated expertise in the field and leadership are viewed as strengths. - The knowledgeable collaborators and consultants listed on the application will provide valuable expertise to the team.