Early Translational II
The ability to direct the differentiation of resident mesenchymal stem cells (MSCs) towards the cartilage lineage offers considerable promise for the regeneration of articular cartilage after traumatic joint injury or age-related osteoarthritis (OA). MSCs can be stimulated in vitro to form new functional cartilage. In the OA-affected joint, the repair is insufficient, leaving a damaged matrix, suggesting that key factors are missing to properly direct the regenerative process. Molecules that activate the chondrogenic potential of cartilage stem cells may potentially prevent further cartilage destruction and stimulate repair of cartilage lesions. Currently there are no disease-modifying therapeutics available for the 40 million Americans suffering from OA. Therapeutic options are limited to oral and intra-articularly injected pain medications and joint replacement surgery. The primary objective of this project is to develop a non-invasive, therapeutic for the regeneration of cartilage in OA. This new therapy will target the resident MSCs in the joint, stimulate production of new cartilage matrix, promote repair and thus limit additional joint damage and improve joint pain and function. To provide a proof-of-concept for our strategy, a cell-based screen of a diverse small molecule library led to compounds capable of enhancing the formation of articular cartilage (chondrogenesis) from MSCs in vitro. In secondary assays, molecules were assessed for protection of the existing cartilage against induced tissue damage. Through these approaches, the lead low molecular weight small molecule PRO1 was identified which promotes cartilage differentiation and protects cartilage from damage. PRO1 reproducibly demonstrated in vivo efficacy in two animal models of OA (surgical and enzyme-induced). OA-associated pain was reduced and the architecture of the cartilage was restored. PRO1 therefore appears to activate the regenerative potential of the resident cartilage stem cells.
Statement of Benefit to California:
Osteoarthritis (OA) is the most prevalent musculoskeletal disease and globally the 4th leading cause of Years Lost to Disease (YLD). OA affects over 40 million Americans and the magnitude of the problem is predicted to increase even further with the obesity epidemic and aging of the baby boomer generation. It is estimated that 80% of the population will have radiographic evidence of OA by age 65 years. The annual economic impact of arthritis in the U.S. is estimated at over $100 billion, representing more than 2% of the gross domestic product. OA accounts for 25% of visits to primary care physicians. In 2004 OA patients received 650,000 knee and hip replacements at a cost of $26 billion. Without change in treatment options 1.8 million joint replacements will be performed in 2015. OA is a painful, degenerative type of arthritis; physical activity can become difficult or impossible. Some patients with osteoarthritis are forced to stop working because their condition becomes so limiting. OA can interfere with a patient's ability to even perform routine daily activities, resulting in a decrease in quality of life. The goals of osteoarthritis treatment are to relieve pain and other symptoms, preserve or improve joint function, and reduce physical disability. Current therapeutic options are limited to pain medications and joint replacement for patients with advanced disease. No disease-modifying OA drugs are approved for clinical use. OA is thus a major unmet medical need with a huge clinical and socioeconomic impact and a complete absence of effective therapies. Clearly the development of a new therapeutic that is both symptom and disease modifying would have a significant impact on the well-being of Californians and reduce the negative economic impact on the state resulting from this highly prevalent disease.
The applicant proposes to achieve a small molecule development candidate, an optimized analog of PRO1, for the stimulation of endogenous stem cells for the treatment of osteoarthritis (OA). In a high throughput screen, the applicant identified PRO1 as a lead candidate for directing the differentiation of human mesenchymal stem cells (MSCs) into chondrocytes, which form cartilage. The proposed therapeutic approach involves injection of the molecule into affected joints to stimulate chondrocyte differentiation from resident MSCs. In Aim 1, the applicant intends to perform a structure-activity relationship (SAR) analysis to optimize the in vitro chondrogenic differentiation and cartilage matrix protection activities of PRO1. The goal of Aim 2 is to demonstrate reproducible in vivo disease modifying activities of PRO1 and its optimized analogues in various animal models of OA. In Aim 3, the applicant will optimize the pharmaceutical characteristics of PRO1 or its analogues, and in Aim 4, identify the cellular target and mechanism of action of PRO1. The reviewers praised the clear objective of this proposal to pursue a regenerative approach for the treatment of OA. The proposed first in class therapeutic has the potential for high impact as it targets a significant unmet medical need. Overall, the reviewers believed the underlying rationale was scientifically and clinically sound, but cautioned that the targeted resident MSC population in diseased joints may not be of sufficient quantity and quality to be meaningfully responsive to the therapeutic. Furthermore, some reviewers thought the rationale behind exploring PRO1 analogues and possibly pursuing several candidates would dilute the team’s effort and perhaps hinder achieving the goal within the proposed three years. Others countered this criticism by asserting that the inherent risk of any therapy based on small molecules is managed in part by identifying and analyzing structurally related molecules. These analogues provide alternatives that may replace the lead compound due to better pharmaceutical properties and/or should it be found to have a poor safety profile. The reviewers appreciated that the application was well written, and milestones were presented clearly with well-crafted success criteria. They commented that the preliminary data strongly suggested that PRO1 was a viable lead candidate for further drug optimization, as it showed preliminary efficacy in two different OA models. Additional strengths included the proposed studies to confirm a potential biomarker for OA, the systematic approach to SAR studies, and the availability of several animal models in the PI’s laboratory. In general, reviewers were convinced of the feasibility of this project to achieve a development candidate in the three year timeframe. The reviewers uniformly praised the Principal Investigator’s (PI) qualifications and track record, and appreciated the PI’s first-hand experience with pharmaceutical development of candidate molecules. Reviewers also praised the research environment at the non-profit applicant institution and the industrial collaboration, which is based on an existing productive relationship. Reviewers believed the proposed budget appeared to be larger than required to accomplish the essential elements of the project, although one reviewer felt the budget was justified to complete the diverse in vivo experimentation necessary for proper evaluation of the lead compounds. Furthermore, one reviewer noted a minor concern that certain key personnel had yet to be identified. In summary, this application targets a regenerative therapy for OA with PRO1 or an optimized analogue, a small molecule development candidate that has been shown to direct MSC differentiation down the chondrogenic pathway. The reviewers were highly enthusiastic about the PI’s excellent credentials, the application’s objective, the thorough research plan, and the convincing preliminary data, and consequently, the review panel recommended this application for funding.