Funding opportunities

Meniscal Repair, Regeneration, and Replacement

Funding Type: 
Early Translational III
Grant Number: 
TR3-05529
Funds requested: 
$7 931 706
Funding Recommendations: 
Not recommended
Grant approved: 
No
Public Abstract: 
Knee joints are composed of different tissues including cartilage, ligaments and meniscus. The meniscus has a role in stabilizing the knee joint and protects cartilage during walking and sporting activities. Damage to meniscus through activity or age-related degeneration are major factors in the development of whole joint diseases like osteoarthritis. This condition is the number one cause of disability in the United States, affecting over 27 million people in the USA alone. Despite substantial developments in surgical techniques, instrumentation, and orthopaedic devices, long-term clinical outcomes are not satisfactory. We propose a multidisciplinary approach by combining our knowledge of human meniscus biology, expertise in stem cell biology and specialized support structures (scaffolds) and tissue regeneration (engineering) to repair torn/damaged meniscus tissue and to regenerate a partial section of meniscus tissue. The objectives include the selection of the appropriate stem cell type, refinement of scaffold with optimal biomechanical properties, and construction of the net shape to aid in surgically implanting the generated meniscus tissue to survive in a knee joint of an appropriate animal model. The ideal combinations of cells and scaffold will be prepared for human clinical trials. Successfully treating meniscal injury and deficiency at an early stage will reduce the incidence of secondary osteoarthritis and lessen the burden on healthcare.
Statement of Benefit to California: 
The menisci are key components of the normal knee joint and loss of a meniscus invariably leads to irreversible joint damage and secondary osteoarthritis (the annual cost of treating osteoarthritis exceeds $120B in the US). Due to lack of intrinsic healing, the standard treatment for meniscal injury is surgical resection which eventually leads to secondary osteoarthritis. Biomimetic meniscal repair that replicates biological, biochemical and biomechanical functions and addresses the major weaknesses in current treatment is more likely to succeed. This application addresses an unmet medical need that, if successfully developed and made available to patients, will represent a significant improvement upon the current standard of care. Successfully treating meniscal injury and deficiency at an early stage will reduce the incidence of secondary osteoarthritis and lessen the burden on healthcare. This grant proposal falls under the mission statement of the CIRM for funding innovative research. A stem cell based approach for treating meniscal lesions is not represented in CIRM’s current Translation Portfolio. This proposal will also expand the field in a new direction and integrate multidisciplinary methods. If successful, this will further validate the significance of the CIRM program and will help maintain California's leading position at the cutting edge of biomedical research.
Review Summary: 
The goal of this Development Candidate (DC) proposal is to engineer a cell-seeded scaffold for repairing tears or defects of the meniscus, a specialized tissue that stabilizes the knee joint and protects cartilage during exertion. Drawing on tools and insights from tissue engineering, meniscal and stem cell biology, the applicant proposes a series of four specific aims: 1) to differentiate bone marrow-derived mesenchymal stem cells (MSC) and induced pluripotent stem cells (iPSC) into meniscal fibrochondrocytes; 2) develop a biomimetic scaffold with properties of native meniscus; 3 and 4) demonstrate ability of the resulting tissue constructs to mediate meniscal repair in vitro and in vivo. Key milestones include selecting the appropriate stem cell type, optimizing the scaffold, establishing model systems, achieving scaled up manufacture that is compatible with good manufacturing practices (GMP), and assessing efficacy and disease modifying activity in a relevant preclinical model. Objectives and Milestones - The proposed research is unlikely to lead to a development candidate due its premature status and diffuse approach. - The milestones are missing many important details, including well-defined criteria for success. - The target product profile (TPP) is unclear in several key attributes, i.e. whether meniscal tears or partial replacements are targeted, whether the product would contain multiple cell types, or whether MSCs/iPSCs would be allogeneic or autologous. Rationale and Significance - Reviewers criticized the rationale for focusing on two types of disease (tear and defects), two possible cell sources, a possible requirement for a third source of cells, and two possible scaffolds types. The downstream implications of these choices are not interchangeable. - Reviewers thought it would be unrealistic and expensive to create a new iPSC line for every meniscal repair. - Meniscal tears and defects, along with their accompanying risk of osteoarthritis, reflect an important and substantial unmet need. The bar for translating the proposed DC in this low risk indication, however, may prove difficult to meet. Research Project Feasibility and Design - Preliminary data was presented in a chaotic manner, making it difficult for reviewers to understand their context and relevance. - The four specific aims do not integrate or mention the five project milestones. Key experimental details were omitted throughout the application. - Reviewers desired additional explanation or data supporting the selection of the preclinical models for meniscal repair. Also, the research plan should have included a long-term proof-of-concept study where the knee safety/pathology and explant evaluation would occur at the end. - The research plan is not sufficiently focused to be feasible within a three-year window. - In the research plan, the rationale for including certain approaches, such as the bioprinting technology, was not sufficiently articulated through discussion or preliminary data. Qualification of the Principal Investigator (PI), Partner PI and Research Team - The research team appears somewhat weighted towards bioengineering and biomaterials expertise with less experience in translational safety issues relating to cell therapy for mild disorders. The team would benefit from an expert in iPSC technology. - The budget seems very high, and sufficient experimental details were not presented for reviewers to determine if the number of preclinical models used in the project contributed to the costs. - The PI is an expert in cartilage biology and translational research and is well placed to lead this study. The Partner PI has relevant expertise in meniscal biology and repair. Collaborations, Assets, Resources and Environment - The environment and resources available to the team appear to be good, although evidence of institutional support has not been provided. - The international collaboration is already in place and is likely to work well. Responsiveness to the RFA No relevant concerns were highlighted by reviewers under this review criterion.
Conflicts: 

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