Early Translational III
Osteoarthritis (OA) is an age-associated disorder affecting a large proportion of the elderly population. Current treatments for OA and cartilage degeneration are surprisingly limited to pain relief or total joint replacement resulting in huge medical costs. In this proposal, we propose to test a potential treatment for OA utilizing stem cells. It has been recently discovered that skin cells can be converted into pluripotent stem cells that resemble embryonic stem cells in their ability to give rise to various cell types. We propose to use these induced pluripotent stem cells to generate cells from patients themselves to effectively treat cartilage defects and avoid rejection upon transplantation. Recent reports have shown that cells from younger donors are more effective at treating cartilage defects than those from older donors. We plan to study young and old cells to identify the specific factors that can be employed to coax the stem cells towards young cartilage cells with a higher capacity for regeneration. We will test the stem cell derived young cartilage cells in appropriate animal models, for their capacity to repair cartilage defects created by surgery. An appropriate animal model is essential to test cartilage regeneration as some animals like mice can undergo spontaneous repair and hence do not faithfully recapitulate the conditions in humans. If successful, our proposed treatment will be a first disease-modifying treatment for cartilage regeneration and OA.
Statement of Benefit to California:
The establishment of CIRM has allowed California to be a front-runner in stem cell research. CIRM funds have helped create an intellectually stimulating scientific environment for stem cell innovation and applications with the potential to improve the quality of millions of patients’ lives. The funds invested by the state of California in multiple private and public institutions in stem cell research have also created significant job opportunities. This research proposal is in response to a call for early translational projects that aim to develop a cell-based therapy for a major unmet medical need. We propose a cell-based therapy for cartilage regeneration for repairing cartilage injuries and age-associated Osteoarthritis (OA). OA affects a large proportion of aged population in California and the rest of US. The only treatment options for OA to date are pain management and total joint replacement leading to a huge medical burden on the US economy. A potential early intervention therapy for cartilage regeneration would delay the progression of disease resulting in huge savings and improving the quality of many a patient' lives.The success of the proposed research could be a first disease modifying treatment for cartilage regeneration and would be a huge medical benefit in California as well as the rest of US.
This Development Candidate Feasibility proposal is aimed at developing a stem cell-derived treatment to repair cartilage damage associated with osteoarthritis (OA). The central hypothesis is that juvenile chondrocytes have greater regenerative ability than older ones. The project will use patient skin samples to develop autologous iPS cells and identify factors that can direct them to become chondrocytes with a juvenile phenotype, referred to as neo-chondrocytes. The project seeks to show proof of concept using these neo-chondrocytes in large animal models to treat OA. Objective and Milestones - Reviewers felt the work proposed was at too early a stage with insufficient data for a translational award, although it was noted that the objectives and aims were well conceived for a discovery project. - Project timeline was viewed as overly aggressive and unrealistic for 3 years Rationale and Significance -The proposed project is based on the theory that juvenile or neo-chondrocytes are superior to adult chondrocytes at regenerating cartilage, however no data have been provided to date showing any in vivo benefit and the in vivo studies planned under this project will not make such a comparison. This is a major flaw in the project. - The project assumes that introducing genes for juvenile chondrocytes into iPSCs will result in neo-chondrocytes that are equivalent to natural juvenile chondrocytes but did not provide any rationale for length of time for this expression (continuous vs one time only). Research Project Feasibility and Design - Reviewers agreed that the design includes a substantial component of early discovery research, such as the identification and validation of key markers for young chondrocytes. - No evidence has been provided that the group can differentiate iPSCs to young cartilage cells - The experimental design lacks detail(s) and raises a number of important concerns regarding the probability of success. Potential problems and alternative approaches are not discussed in any significant detail, and this is an additional weakness to the grant proposal. Qualification of the PI (Co-PI and Partner PI, if applicable) and Research Team - PI has strong expertise in iPSC derivation and epigenetic research, but no apparent experience with chondrogenesis or osteoarthritis. - While the team has the appropriate expertise for the project, some reviewers were concerned about the lack of translational research experience. Collaborations, Assets, Resources and Environment No relevant concerns were highlighted by reviewers under this review criterion Responsiveness to the RFA - Reviewers questioned the responsiveness of this application due to the emphasis of the research plan on basic research focused activities (thus not a DCF).