Early Translational I
$3 118 431
Statement of Benefit to California:
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.