Directed differentiation of MSCs by a novel biologic to promote cartilage repair

Funding Type: 
Disease Team Research I
Grant Number: 
ICOC Funds Committed: 
Public Abstract: 

The ability to direct the differentiation of resident mesenchymal stem cells (MSCs) towards the cartilage lineage offers considerable promise in regenerative medicine of articular cartilage after traumatic joint injury or aging-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 key factors are missing to properly direct the regenerative process. Molecules that activate this potential of cartilage stem cells potentially can 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, universal therapeutic for the regeneration of cartilage at any stage of 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.

From cell-based screens of a unique library of secreted proteins, novel candidates enhancing the formation of articular cartilage (chondrogenesis) from MSCs in vitro were identified. In secondary assays, proteins were assessed for protection of the existing cartilage against induced tissue damage. Through these approaches, the proposed biologic therapeutic OTX-75 was identified to potently promote cartilage differentiation and protect cartilage from inflammatory mediators. Following intra-articular injection in mouse and rat knees, OTX-75 localized to the pericellular matrix, thus reaching the cells in the joint cartilage. OTX-75 did not cause any unwarranted effects in joint tissues or immune responses after 4 weeks. We determined that the chondrogenic activity localizes to the C-terminal domain and subsequently solved its crystal structure. Here we aim to demonstrate the ability of OTX-75 to repair cartilage in vivo in experimental OA in rat, and 2 large animal models. We will characterize the biological activities and identify the binding partners of OTX-75 and its C-terminus as a potential back-up strategy to minimize off-target effects or systemic toxicity. This protein will be developed to meet therapeutic production standards for use in humans and verified for the lack of adverse events. The development of specific biomarkers will allow monitoring of mechanism of action-based efficacy in vivo. These data and reagents will allow the filing of an Investigational New Drug application by the end of the funding period. Successful completion of the program has the potential to lead to the first effective disease-modifying therapy for the approximate 7% of the US population suffering from osteoarthritis.

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. It 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 and working can become difficult or impossible. Some patients with osteoarthritis are forced to stop working because their condition becomes so severe and 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. The OA problem is thus unparalleled with its clinical and socioeconomic impact and a complete absence of effective therapies.

This proposal is aimed at advancing a novel disease-modifying OA drug to the clinic within 4 years. The candidate therapeutic mitigates the underlying cause of OA – specifically joint destruction from abnormal activation and differentiation of cartilage cells. This therapeutic has been developed to act on the resident stem cells, already present in the joint of both normal and diseased joint cartilage, and stimulate the regeneration of cartilage – leading to the improvement of joint function. The development of the novel therapeutic that improves the symptoms and underlying causes of OA would have a significant impact on the well-being of patients and reduce the economic impact resulting from this highly prevalent disease.