Tissue Collection for Disease Modeling
Reprogramming of patient derived somatic cells into iPSCs opens the possibility for personalized medicine and drug testing. Genetic diseases responsible for the manifestation of disease can be “modeled” by re-differentiation of iPSCs into the cell lineages of interest, primarily those affected by each particular disease. As such, patient-derived iPSCs hold promise not only for regenerative medicine but also for the elucidation of complex molecular mechanisms ultimately responsible for pathological manifestation. Disease modeling subsequently presents the possibility for in vitro drug discovery, testing and development of personalized therapies. Many efforts aim to identify the earliest signs of Diabetic Kidney Disease (DKD) so that treatments can be instituted before irreversible renal injury occurs. Considering that Diabetes Mellitus (DM) now accounts for more cases of end-stage renal disease (ESRD) than any other cause of chronic kidney disease (CKD) and that no treatment apart from renal replacement is available, modeling disease with patient-derived iPSCs represent the most innovative approach for the development of novel therapeutics targeting the kidney. We will obtain up to DKD1000 + 100 control human samples suitable for reprogramming into iPSCs. The generated iPSCs will represent an invaluable platform for the study, and treatment of renal pathologies as well as shed new light on our understanding of these complex diseases and the causative role that Diabetes plays.
Statement of Benefit to California:
The California Institute for Regenerative Medicine (CIRM) was established in 2004 with the passage of Proposition 71, which provided $3 billion in funding for stem cell research at California universities and research institutions to advance stem cell research and develop therapies to relieve human suffering. Eight years later, the creation of a culture for the Medicine of the 21st century, as reflected by the many similar initiatives initiated world-wide, is already a clear indication of success. Our position is that curing diseases and perfecting technologies that allow for the development of novel therapies will boost CIRM’s success. The present RFA on Tissue Collection for disease modeling is an example of the far-reaching objectives of CIRM’s initiative, a way of embracing life science disciplines into a multidisciplinary program with the ultimate goal of developing novel therapies. We see three direct, major positive effects for Californians: (1) Patients in California will be privileged once actual therapies are developed and ready to move to the bedside. (2) California will witness the growth of its technological/industrial infrastructure to develop new forms of treatment. (3) California will establish itself as a world-wide reference for the banking and generation of stem cell models of disease. The combination of the above-mentioned factors is powerful and dividends will be generated in the form of revenues from health care delivery and intellectual property.
Chronic kidney disease (CKD) is a debilitating condition that often results from complications of diabetes and/or vascular disease. This proposal focuses on tissue collection from 1000 CKD patients from a large ex-US renal treatment center. The samples will be collected from 600 patients with diabetic nephropathy, 400 with vascular nephropathy and 100 control individuals, and transferred to the Deriver for the generation of induced pluripotent stem cells (iPSC). The applicant envisions that in future studies, iPSC will be differentiated to podocytes, specialized epithelial cells crucial to maintaining healthy renal filtration function. With the underlying hypothesis that early damage to the podocyte is the key initiating event in CKD, such iPSC-based models would be used for research and drug discovery platforms targeting early and potentially reversible events in CKD. Impact and Significance - The proposed ex-US patient cohort diminishes the potential impact and significance of the proposal, as it does not adequately represent the California population. Further, based on the demographics of that center, it is not likely to include a sufficient number of African Americans, who are at particularly high risk for CKD. - CKD places an enormous burden on the health care system and there is no effective means of halting its progression to end-stage renal disease. - Current research models do not recapitulate human renal physiology or the cellular events underlying CKD, a genetically complex disease. Thus, an iPSC-based model and drug screening platform for CKD would be significant and have widespread impact. Rationale - The collected samples will be unique as there are no cell lines available to model chronic kidney disease. - There is very little published data or preliminary results to support the feasibility of iPSC differentiation to podocytes or to support the concept of focusing exclusively on the podocyte for modeling CKD. Overall, reviewers were unclear whether the targeted disease is amenable to iPSC-based modeling. - The applicant referenced candidate gene polymorphisms that have been linked to diabetes related CKD. One reviewer questioned the relevance of these genes to in vitro studies of kidney cells to model CKD, citing that most experimental evidence supports a role for these genes in the insulin-producing beta cell. Quality of the Proposed Protocols - The investigators propose to access an existing patient database system that includes 10,000 patients. The approach, however, to select CKD patients for inclusion in this Initiative was not clearly developed or explained and inclusion/exclusion criteria were not described. - The proposal contained insufficient information to determine whether the health information of participants will be adequately managed, coded, and protected in accordance with all relevant state and federal laws and regulations and with CIRM regulations. - The applicant provided a consent form template that meets the goals of this RFA, but it needs to be updated to be specific to the proposed protocol. Feasibility - The proposed center would provide the patient volume to allow procurement of blood samples from the proposed 400 individuals with vascular nephropathy and 600 with diabetic nephropathy. - There was no justification given for the choice of the proposed sample number(s). Budget - The travel budget is large to accommodate monthly travel of multiple participants between the ex-US center and California. Qualifications of the Principal Investigator (PI) and Team Members, Resources - The PI is an experienced investigator and accomplished leader in stem cell biology and regenerative medicine with the credentials to lead the team and the project. - The ex-US clinical center and the California research center have exceptional resources. - There is little experience amongst the proposed team (or elsewhere in the world) with directed differentiation of human iPSC into podocytes or other renal lineages.