Funding opportunities

Embryonic Stem Cell-Derived Chondroprogenitor Cells to Repair Osteochondral Defects

Funding Type: 
Disease Team Therapy Development III
Grant Number: 
DR3-07078
Funds requested: 
$13 423 503
Funding Recommendations: 
Recommended if funds allow
Grant approved: 
No
Public Abstract: 
Arthritis is a common disease and increases with age. The annual cost of treating arthritis in the US is estimated to be over $200B in 2013. Over a million joint replacements are performed in the US alone for end-stage arthritis. However, for younger patients with severe arthritis or impending arthritis there is no treatment that can prevent, cure, or even slow the progression of this disease. In this proposal we target the repair and regeneration of knee cartilage and underlying bone defects (lesions) that if are left untreated are a major factor in contributing to early osteoarthritis in patients less than 55 years of age. Our approach is to advance a third-generation cell therapy by combining stem cells with a natural hydrogel scaffold to support the repair cartilage and bone defects. This application proposes a multicenter collaboration. Each center contributing key expertise toward this project effectively span the translational bridge between basic science and the clinic. We have assembled a development team consisting of translational scientists; physicians with expertise in multi-center clinical trials; four adult knee reconstruction surgeons; stem cell biologists; three members of the FDA Cellular, Tissue and Gene Therapies Advisory Committee; a rheumatologist; a musculoskeletal radiologist; a biostatistician; and a biomechanist. We propose to conduct the following “investigational new drug” IND-enabling activities. Manufacture and Characterize cell lines and scaffold under clinically approved conditions Conduct preclinical proof of concept, dosing, and mechanism action studies Two animal model species will be used following Guidance for Industry. Small and large animal models based on anticipated reaction of these animal to human cells, as well as the biological and biomechanical relevance, and FDA recommendations. This will facilitate accurate assessment of the cell/scaffold dose and route of administration. Conduct Safety Studies In our animal models, we will study short-term, long-term, and delayed-onset toxic or adverse responses to the implanted cells. We will examine the knee and the entire body for cell death, tumor formations and durability of the regenerated tissue, and whether the regenerated tissue is normal. If this approach is successful this will be the first-in-man embryonic stem cell-based treatment of an orthopaedic disease that has challenged repeated attempts over the last 400 years.
Statement of Benefit to California: 
Arthritis is a common disease and increases with age. The annual cost of treating arthritis in the US is estimated to be over $200B in 2013. Over a million joint replacements are performed in the US alone for end-stage arthritis. However, for younger patients with severe arthritis or impending arthritis there is as yet no treatment that can prevent, cure, or even slow the progression of this disease. In this proposal we target bone and cartilage defects that are a major factor in contributing to early osteoarthritis in patients less than 55 years of age. Our approach is to advance third-generation cell therapy by constructing scaffolds that are seeded with chondroprogenitor cells programmed to undergo differentiation into bone and cartilage cells. This proposal falls under the mission statement of CIRM for funding innovative research. A stem cell based approach for treating articular cartilage defects in not represented in CIRM’s current portfolio. If successful this will be the first-in-man embryonic stem cell based treatment of an orthopaedic disease that has challenged repeated attempts over the last 400 years. This will further validate the significance of the CIRM program and help maintain California’s leading position at the cutting edge of biomedical research
Review Summary: 
EXECUTIVE SUMMARY This project proposes to treat focal cartilage defects using an embryonic stem cell-derived cartilage precursor cells in combination with a hydrogel scaffold. Applicants propose to 1) complete the manufacturing and characterization of the cell lines and hydrogel scaffold; 2) conduct preclinical proof of concept, dosing and mechanism of action studies; and 3) complete safety studies in preclinical models. This Early Translational Allowance Pathway application has the goal of completing all preclinical studies and filing an Investigational New Drug (IND) application with the Food and Drug Administration within the award period. Significance and Impact - Reviewers were concerned about the ability of this approach to be clinically competitive. Focal cartilage lesion is a problem with alternative treatments already marketed or in development, including cell-based therapies. The standard of care surgical treatment, known as microfracture, is successful, at least for several years, in a high percentage of patients, so the approach will have to show substantial benefit over alternatives to have an impact on patient care. - The application is responsive to the RFA in that an existing Early Translational awardee is proposing to complete an IND filing to apply human pluripotent cells to treat cartilage defects. Scientific Rationale and Risk/Benefit - While there appears to be good scientific rationale and preliminary data to support the approach, reviewers were concerned whether the risks are justifiable for using a pluripotent cell-derived product to treat a non-life threatening condition for which there are other treatment options available. Therapeutic Development Readiness - Reviewers were impressed by the preliminary data, which included a comparison of the development candidate against other therapeutic cell types in an animal model of cartilage defect. - Given the potential risks if any undifferentiated cells remained in the product after transplantation, insufficient details were provided regarding the manufacturing process and test methods that will be utilized. - A good regulatory strategy is in place. Design and Feasibility - The project plan is reasonable and can likely be completed within the proposed timeline. - The proposed milestones are reasonable and should provide reliable indicators of progress. -The proposed preclinical studies are appropriate and should be adequate to support regulatory approval. However, it was suggested that patients who have failed microfracture might be a more appropriate patient population to consider for the proposed clinical trial. - The delivery strategy is not consistent with the surgical procedure for the current standard of care, so reviewers were concerned that the current experimental design and preclinical studies would hinder later stage clinical development activities. -It was pointed out that transfer of the technology to the manufacturing facility has not yet been completed. After that transfer, studies may need to be performed to demonstrate comparability with data collected thus far. Principal Investigator (PI), Development Team and Leadership Plan - The PI and team were viewed as qualified to perform the proposed studies. - There was some concern expressed regarding whether the identified Regulatory Lead was sufficiently experienced in that role. Budget - While overall the budget was viewed as appropriate and justified, some reviewers noted that the budgets proposed for manufacturing and the quoted estimate from the Contract Research Organization were high considering the scope of activities. Collaborations, Assets, Resources and Environment -The appropriate collaborations and assets are in place. It did not appear, however that technology had yet been transferred to the facility that will be manufacturing the cells.
Conflicts: 
  • Joy Cavagnaro

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