Early Translational I
Arthritis is the result of degeneration of cartilage (the tissue lining the joints) and leads to pain and limitation of function. Arthritis and other rheumatic diseases are among the most common of all health conditions and are the number one cause of disability in the United States. The annual economic impact of arthritis in the U.S. is estimated at over $120 billion, representing more than 2% of the gross domestic product. The prevalence of arthritic conditions is also expected to increase as the population increases and ages in the coming decades. Current treatment options for osteoarthritis is limited to pain reduction and joint replacement surgery. Stem cells have tremendous potential for treating disease and replacing or regenerating the diseased tissue. This grant proposal will be valuable in weighing options for using stems cells in arthritis. It is very important to know the effect of aging on stems cells and how stem cell replacement might effectively treat the causes of osteoarthritis. We will establish conditions for stem cells to repair a surgical defect in laboratory models and test efficacy in animal models of cartilage defects. We will demonstrate that stem cells have anti-arthritic effects, establish optimal conditions for stem cells to migrate into the diseased tissue and initiate tissue repair, and test efficacy in animal models of arthritis. We will plan safety and efficacy studies for the preclinical phase, identify collaborators with the facilities to obtain, process, and provide cell-based therapies, and identify clinical collaborators in anticipation of clinical trials. If necessary we will also identify commercialization partners. Stem cells fight disease and repair tissues in the body. We anticipate that stem cells implanted in arthritic cartilage will treat the arthritis in addition to producing tissue to heal the defect in the cartilage. An approach that heals cartilage defects as well as treats the underlying arthritis would be very valuable. If our research is successful, this could lead to first ever treatment of osteoarthritis with or without stem cells. This treatment would have a huge impact on the large numbers of patients who suffer from arthritis as well as in reducing the economic burden created by arthritis.
Statement of Benefit to California:
California has been at the forefront of biomedical research for more than 40 years and is internationally recognized as the biotechnology center of the world. The recent debate over the moral and the ethical issues of stem cell research has hampered the progress of scientific discoveries in this field, especially in the US. The CIRM is a unique institute that fosters ethical stem cell research in California. The CIRM also serves as an exemplary model for similar programs in other states and countries. This grant proposal falls under the mission statement of the CIRM for funding innovative research. The proposal will generate highly innovative and effective therapies for cartilage degeneration and osteoarthritis and will explore the potential use of tissue-engineered products from stem cells. 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. Reducing the medical and economic burden of large numbers of patients who suffer from arthritis would is of significant benefit.
This development candidate proposal will use stem cells (SCs) for cartilage regeneration and osteoarthritis treatment. The investigators will attempt to induce human pluripotent cell-derived chondrocyte progenitor cells (CPCs) to migrate into and repair damaged cartilage. To select the best cell source for development, the abilities of CPC derived from human induced pluripotent stem cells (iPSC) and human embryonic stem cells (hESC) to repair damaged normal and osteoarthritic cartilage explants will be compared. Investigators will optimize conditions to induce CPC differentiation, repopulation and repair of both focal cartilage defects and osteoarthritic cartilage in vivo. Lastly, the investigators will plan preclinical safety and efficacy studies using IND-enabling arthritis models in collaboration with a cGMP compliant facility and identify potential clinical collaborators and commercialization partners. The investigators expect CPCs to fill focal cartilage defects as well as migrate into and repopulate osteoarthritic cartilage, a development that would represent the first disease-modifying treatment for osteoarthritis. The reviewers were very enthusiastic about this proposal. Development of a disease modifying treatment for focal cartilage injury and osteoarthritis addresses a major unmet medical need. If successful, this developmental candidate could reduce the need for knee arthroplasty and significantly enhance quality of life for many. The proposal is well written and contains excellent figures and schematics. Reviewers universally appreciated the preliminary data demonstrating chondrogenic differentiation, matrix secretion and ex-vivo closure of cartilaginous defects with hESC derived chondroprogenitor cells. This solid foundation increases the likelihood of a successful program. The well-designed experimental plan follows a logical progression. In addition, the animal models are well characterized and well suited to studying outcome. Criteria for success (International Cartilage Repair Society scores) are appropriate. One reviewer felt that the choice of CPC aggregates, while interesting, merited further explanation. It was noted that within the limits of existing technology, focal cartilage defects might be easier to treat than the diffuse damage seen in osteoarthritis. Timelines and milestones are well described and achievable. While the reviewers agreed the proposal was ambitious for the time frame, they noted that even if all the goals of the proposal weren’t met, these studies would move the arthritis field significantly forward. An exceptional team with expertise in all fields required for the program to succeed, including orthopedics, rheumatology, cell biology, stem cell biology, stem cell transplantation and statistics, has been assembled. The team also has access to the necessary biopsies to proceed with the studies outlined in the plan. Facilities, environment and resources are outstanding. Despite strong support for the proposal, reviewers agreed that the request for cGMP funding was probably premature. This proposal addresses the large unmet medical need of cartilage repair with both a well-designed experimental plan and an appropriate set of criteria for disease modification. The strong preliminary data provided additional confidence that goal of the proposal can be achieved. Although the plan is ambitious, the assembled team has the multidisciplinary expertise required for its successful execution.