Funding opportunities

Stem Cells for Treating Pre-Arthritic Focal Cartilage Defects

Funding Type: 
Disease Team Research I
Grant Number: 
Funds requested: 
$18 028 444
Funding Recommendations: 
Not recommended
Grant approved: 
Public Abstract: 
Arthritis is a disabling condition that afflicts 6 million Californians and costs our state nearly $32 billion a year for health care and lost wages. Yet arthritis remains an unmet medical need and its overall impact will increase steadily given that more of the population is aging and that the inability to maintain an active lifestyle has severe consequences for many aspects of health. Sixty million Americans are projected to have arthritis by 2020. In the absence of effective 'arthritis drugs', joint replacements offer some relief but have limited durability and are unsuitable for young patients. Other treatments that try to repair cartilage damaged prior to arthritis, such as microfracture of underlying bone or cartilage cell transplantation, fail to restore native mechanical and biological properties of the joint and do not avoid disease progression. For preventing arthritis, stem cells have obvious appeal, but directing them to synthesize a desirable cartilage matrix has proven challenging. We have made a fundamental advance in overcoming limitations to the use of stem cells for cartilage repair. We have developed a Product in which human mesenchymal stem cells (MSC) are grown alongside highly instructive juvenile cartilage cells. These cells are arranged in bilaminar cell pellets (BCPs), and embedded in a mechanically functional biomaterial composite. BCPs synthesize abundant articular cartilage matrix, adapt to the unique environment of the joint, and resist inflammation. The biomaterial composite retains the BCPs at the defect site and supports joint forces. Over time BCPs will secrete cartilage matrix and replace the biomaterials. We propose a focused plan to optimize the cell source and BCP interactions with biomaterials; establish cell banks; demonstrate feasibility, safety, and efficacy; and develop clinical trial and commercialization plans. Our goal is to accelerate translation of this novel stem cell-based therapy to provide an early intervention for preventing and treating arthritis. With support of a CIRM Disease Team Planning Grant, we assembled an outstanding team of experts from Academia and Industry with the experience and motivation to achieve our goal. The team leader is Director of an industry-collaborative center and an Orthopaedic Biomechanics Laboratory, and a pioneer of protocols for turning stem cells into cartilage. Our Academic partners bring world-recognized leadership in stem cell and skeletal biology, and clinical expertise in orthopaedic surgery, including past clinical evaluations of other cell-based therapies. Our Industry partners have established products for clinical applications, and contribute expertise in cell sourcing, biomaterials, manufacturing, and regulatory processes. By combining the creativity and innovation of Academia with the pragmatic focus of Industry, our team is poised to meet the challenge of filing an IND within 4 years for a stem cell-based therapy for cartilage regeneration.
Statement of Benefit to California: 
Approximately 6 million adults in California, or 27% of the population have some form of arthritis. This disease costs California nearly $32 billion each year, with an estimated $23.2 billion spent on direct medical care and $8.3 billion due to lost wages. The centers for Disease Control and Prevention projects that 60 million people nationwide will have arthritis by 2020. Osteoarthritis is a disabling disease that limits the ability to engage in the regular physical activity that prevents obesity, diabetes, and cardiovascular disease. Consequently, successful development of improved arthritis therapies will benefit a significant portion of the California population. Additionally, we anticipate that the management structure of this program along with the cell/matrix technologies can ultimately be applied to a host of other musculoskeletal diseases such as back pain, osteoporosis, and fracture repair. In addition to the health of Californians, cell based therapies for arthritis and other musculoskeletal conditions provide a huge commercial opportunity for California industry. Credit Suisse has estimated that the growth potential for the orthopaedic industry focused on hip and knee treatment is positive, with projected global sales expanding from $9.6 billion in 2006 to $13 billion in 2011. The orthobiologic market that includes regenerative technologies currently accounts for roughly 12% of the worldwide orthopaedic implant market and is the fastest growing segment, at 20% annually. Our Team partners with several California companies who will directly benefit from this effort. Clearly their economic success will provide employment opportunities for Californians, tax revenue for the state, and help maintain California as a world leader in biotechnology research and development. This work also aids the research enterprise of California universities by augmenting our competitiveness for NIH funding. This, in turn, brings the brightest scientific talent to the state, fuels innovation, and ensures continued California leadership in the biotech industry. Given the significant unmet clinical need, market opportunity, and rapidly evolving technologies, we anticipate that stem-cell based therapies for arthritis will be realized in the next 4 to 8 years. The CIRM Disease Team Award can assure that this important therapy with the potential to prevent the progression of osteoarthritis is developed in California.
Review Summary: 
Osteoarthritis (degenerative arthritis) is a common, painful and debilitating condition with limited treatment options. It is caused by breakdown and eventual loss of articular cartilage (cartilage of the joints), often resulting from joint injuries. The objective of this proposal is to develop a stem cell-based therapy for repair of pre-arthritic focal cartilage defects in order to prevent progression to osteoarthritis. This will be achieved using co-cultures of autologous adult mesenchymal stem cells (MSC) and allogeneic juvenile chondrocytes combined in structured bilaminar cell pellets (BCP). The rationale is that the chondrocytes in the BCP will persist for a period of time and instruct MSC to differentiate into chondrocytes and secrete cartilage to repair the damaged joint. The BCPs will be embedded in a mechanically functional biomaterial composite consisting of a hydrogel/scaffold carrier, designed to deliver and retain BCPs at the knee cartilage repair site as well as possibly provide mechanical stability during the recovery process. Thus the therapeutic candidate will consist of BCPs embedded in a biomaterial composite. Initial project goals include the development of protocols for isolating and expanding MSCs from either bone marrow or adipose tissue; development of a protocol for isolating juvenile chondrocytes; development of a manufacturing process for BCPs; and development of a hydrogel/scaffold with tensile properties similar to native cartilage. Subsequent goals include conducting safety and efficacy (proof-of-concept) studies in preclinical models. Early interactions with the Food and Drug Administration (FDA) will be conducted and FDA recommendations will be incorporated into the preclinical plan. A major criticism of this proposal is related to its complexity, since the proposed therapeutic candidate involves two cell types plus hydrogel plus scaffold. This poses significant hurdles in terms of manufacturing and clinical logistics and makes the regulatory path extremely difficult. A second major criticism involved doubts regarding the scientific rationale which was viewed as not compelling. A third problem was the lack of any proof-of-concept data with respect to disease-modifying activity. An Investigational New Drug (IND) application in four years was considered unlikely. Although the reviewers accepted that if successful, this project may yield a cell therapy that will significantly improve the outcome of patients with a debilitating disorder, they questioned the basic scientific premise that this complex product offers a significant advantage over other, less complex options. The complexity lies in the use of two cell types, autologous MSC and allogeneic juvenile chondrocytes, with a further layer of complexity added by the potential use of a hydrogel/ scaffold. Reviewers agreed that this is a high risk project, and while there is some scientific rationale for the use of this complex technology they were not convinced it has been effectively justified, since the design of relevant preliminary experiments was flawed. Although these experiments compared the BCP combination cultures to each cell type alone, they did not include the standard published condition, MSC plus TGFbeta. Therefore, reviewers found that the evidence favoring BCP over existing simpler approaches (such as TGFbeta-stimulation of MSC alone), is unconvincing, and suggested that there may be no need to move from a simple single cell/growth factor system to a complex two-cell autologous/allogeneic system. Reviewers also had doubts regarding the conclusion that BCP co-cultures promote chondrogenic differentiation of MSC as evidenced by the detection of chondrocyte-specific transcripts in the cultures. They commented that it was unclear if those transcripts were, in fact, derived from the juvenile chondrocytes in the co-culture rather than from differentiated MSC-derived cells. Taken together, these doubts regarding the basic scientific rationale were considered to be a major weakness of the proposal. Reviewers felt that the plan is logical and most of the milestones are timely and meaningful. The proposed clinical indication, treatment of small, non-arthritic focal lesions, is an excellent context in which to test the underlying assumption that addition of cartilage forming cells to an area of localized damage will be sufficient to effect repair. The reviewers commended the applicant for including an early interaction with the FDA and viewed the early and continuing focus on regulatory concerns and FDA interactions as particular strengths of the proposal. However, the reviewers had multiple concerns that led them to doubt an IND could be achieved in four years. They commented that the preclinical data are limited and the project seemed to be still early and undefined. For instance, the final product has yet to be established and the plan to compare the effects of various hydrogel/scaffold combinations is interesting but does not lend itself well to product development. Also, because the applicant has not yet demonstrated disease-modifying proof-of-concept activity, the data appear not to be sufficiently mature for a development project. It was felt that the manufacturing goals are overly ambitious and would be subject to delay. For example, sourcing juvenile knee cartilage may be more difficult than anticipated, due to limited availability and competition for this resource. From a regulatory standpoint, the use of an allogeneic/autologous two-cell system raises concerns about cell-cell interactions which the proposal did not address. One reviewer expressed doubts that the FDA would allow this to go forward. Another reviewer expressed concern regarding the proposal’s approach to immune rejection and questioned the applicant’s conclusion regarding the likelihood of immune tolerance in this system. This reviewer commented that there was no detailed analysis of the degree of Major Histocompatibility Complex (MHC) mismatching, which would influence the extent of any immune response. Since patients with focal cartilage defects do not have a life threatening end-stage disease, the risk of lifelong immunosuppression would likely not be tolerated in this population. Therefore this is a key issue for this clinical target. Collectively, the multidisciplinary research team represents an appropriate mix of basic and clinical research together with management skills to ensure progress of the project, and the Collaborative Funding Partner adds significant value. The PI has the necessary experience to manage a project of this magnitude and scope and clearly understands the importance of effective technology transfer of documented methods and has allowed appropriate time for these processes. The leadership plan appears well conceived and should ensure coordinated activities across the team to enable effective monitoring of progress against milestones, implement strategic decisions and resolve potential conflicts. In general the budget seems appropriate. The budget, however, reflects continuing expenditure. Reviewers also questioned the justification for a confocal microscope since results from confocal imaging analyses are not cited as one of the product evaluation criteria. In summary, reviewers commented that the proposed indication is an excellent context to test the hypothesis that the addition of cartilage-forming cells will be sufficient to effect repair and that the addition of a matrix to provide structural stability is an added potential benefit. However, they were unconvinced regarding the scientific rationale for the proposed two-cell system and overall, the complexity of the proposed therapeutic product was a major concern with respect to manufacturing and clinical logistics as well as the regulatory path. There was agreement that this proposal seemed premature and unlikely to achieve the objective of filing an IND within four years.

© 2013 California Institute for Regenerative Medicine