Early Translational II
Arthritis is a disabling condition that afflicts 6 million Californians and costs our state nearly $32 billion a year in healthcare 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 construct 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 an FDA-approved biomaterial. BCPs synthesize abundant articular cartilage matrix, adapt to the unique environment of the joint, and resist inflammation. The biomaterial retains the BCPs at the defect site while, over time, BCPs secrete cartilage matrix to replace the biomaterial. We propose a focused plan to optimize BCP interactions with the biomaterial; demonstrate feasibility, safety, and efficacy; standardize cell isolation, and create a product development plan. 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 partner has established products for clinical applications, and will contribute expertise in cell sourcing, 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 generating pre-clinical data that will support future IND-enabling studies.
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. Both our subcontractors (PCT and ISIS) 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 Early Translational Research Award can assure that this important therapy with the potential to prevent the progression of osteoarthritis is developed in California.
This application for a Development Candidate Award focuses on an allogeneic cell therapy for focal articular cartilage injury of the knee. The applicant has developed a construct consisting of autologous mesenchymal stem cells (MSCs) and allogeneic juvenile chondrocyte progenitor cells, arranged in bilaminar cell pellets (BCPs) and embedded in an FDA-approved biomaterial. MSCs have the potential to differentiate into tissues other than cartilage and are not effective when implanted alone into injured cartilage. The applicant presents preliminary data suggesting that co-culture of MSCs with juvenile chondrocyte progenitors in BCPs promotes their differentiation into chondrocytes. The applicant proposes to advance these BCPs toward clinical translation in four Specific Aims: (1) to test BCPs in an animal model to ensure that their desired featured are maintained in vivo and to establish the target cartilage defect size; (2) to optimize manufacturing and scale-up of MSCs, juvenile chondrocyte progenitors and BCPs; (3) to assess the efficacy and safety of BCP transplant in a large animal model of cartilage injury; and (4) to develop a clinical strategy and development plan. Reviewers agreed that this proposal addresses an unmet medical need but felt that the potential impact was overstated. The applicant uses osteoarthritis data to illustrate the potential benefit of BCP therapy but osteoarthritis is not the target indication, although it can eventually result from focal knee cartilage injury. Nonetheless, the reviewers agreed that an improved therapy for focal cartilage injury is an important goal. They also agreed that there is scientific rationale for pursuing BCPs to address the problems associated with the implantation of MSCs alone. However, they weren’t convinced that BCPs would necessarily be an improvement and noted that the research plan is not designed to test this hypothesis. Reviewers were also concerned that the applicant proposes allogeneic transplant of juvenile chondrocyte progenitors and assumes that they won’t be subject to immune rejection. The reviewers noted that while there is some evidence that allogeneic cartilage implants are immune privileged, the evidence for isolated chondrocytes is much less compelling. In addition, while MSCs may suppress immune rejection, the MSCs in BCPs will presumably undergo chondrogenesis and may not retain their immunomodulatory properties. Reviewers also commented that certain aspects of the proposal are explicitly out of the scope of this RFA, including the large animal GLP pharmacology/toxicology and tumorigenicity studies. The reviewers raised some significant concerns about the research plan and preliminary data. Specifically, they noted that the applicant does not present strong evidence for the superiority of the BCP approach. For example, preliminary data demonstrate greater expression of cartilage associated genes in BCPs versus the positive control, MSCs treated with TGF-beta, however the MSC/ TGF-beta gene expression data is not in line with other publications and appears to show that TGF-beta treatment of MSC had minimal/no effect on the expression of two cartilage associated genes. Reviewers found this puzzling and would have appreciated stronger evidence of efficacy for the BCP approach. They also raised concerns about the proposed animal models. Reviewers weren’t sure that optimization of the complex transplant model proposed in immunocompromised rats would translate to the intended route of administration. They were also concerned that immune rejection caused by xenotransplantation into the large animal model was not addressed in detail. Reviewers suggested that, while the proposed animal model is considered the gold standard by the FDA, the applicant might be better served by doing initial proof-of-concept studies in rabbit, or to avoid issues associated with xenotransplantation, allogeneic transplants in pigs with defined MHC haplotypes. Reviewers praised the strong research team and noted that the Principal Investigator (PI) has a strong translational track record. They appreciated that the co-PI contributes considerable expertise in cell and molecular biology as well as stem cell biology. Reviewers did comment that the team would benefit from the addition of an experienced immunologist who could assist in the design of pre-clinical animal studies. Overall, while reviewers appreciated the goal of this proposal and the experienced research team, they had significant questions about the scientific rationale and the research plan, which reduced their enthusiasm for the proposed therapy. PROGRAMMATIC REVIEW A motion was made to move this application into Tier 1, Recommended for Funding. Reviewers reiterated the previously discussed key scientific issues. As no programmatic reason was advanced to support moving the project up, the motion was withdrawn.