Funding opportunities

A CIRM Disease Team for the Repair of Traumatically Injured and Arthritic Cartilage

Funding Type: 
Disease Team Planning
Grant Number: 
DT1-00656
Principle Investigator: 
Funds requested: 
$55 000
Funding Recommendations: 
Recommended
Grant approved: 
Yes
Public Abstract: 
Arthritis is a disabling condition that afflicts 6 million Californians, costing our state nearly $32 billion annually for health care and lost wages. Given the growth of an aging population encouraged to maintain an active lifestyle due to the overall health benefits, the impact of arthritis is expected to increase significantly. For example, the Center for Disease Control projects that 60 million people nationwide will have arthritis by 2020. The goal of this Disease Team Proposal is to plan an accelerated translation of stem cell therapies for cartilage repair that will provide an early intervention to prevent and treat arthritis. The proposed cartilage regeneration program builds upon the institutional applicant’s world-recognized leadership in stem cell and skeletal biology, and the clinical expertise of the orthopaedic surgery. In addition, strong partnerships with California industry will facilitate successful implementation of clinically beneficial strategies. The team leader is the director of both an industry-collaborative center and an orthopaedic biomechanics laboratory, and a pioneer of new protocols that direct stem cells to make cartilage. Our multidisciplinary team members at {REDACTED} research institutions have well-established interactions that serve as the foundation of our program to propel translation of stem cell therapy. The majority of team members are affiliated with a center focused on cartilage repair and regeneration which fosters such collaborations. In fact, we are already executing pre-clinical studies to assess the potential of stem cells to repair cartilage, and human clinical trials using a patient’s own cartilage cells to treat cartilage erosions. In addition to advancing novel treatments, our team includes international leaders in the development of novel imaging technologies to track implanted stem cells and cartilage repair. These non-invasive imaging techniques will be critical for assessing early success in large animal studies and human clinical trials. Successful completion of this Disease Team Award will result in the development of a non-invasive imaging technology for early detection and localization of cartilage erosions, and a minimally invasive stem cell-based treatment that can be used to heal cartilage and prevent arthritis progression. Such a treatment option does not currently exist. This CIRM Disease Team Planning Grant will assemble experts in all areas necessary for realizing clinical translation, and define milestones to coordinate, motivate, and accelerate development of a stem cell-based therapy for cartilage regeneration.
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. 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. Our Planning Team will represent of a variety of California companies who will directly benefit from this effort. Clearly their economic success will provide employment opportunities for Californians, tax revenue for the state, and help maintain {REDACTED} 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 Disease Team Initiative can assure this occurs in California.
Review Summary: 
Executive Summary The PI proposes to establish a diverse multidisciplinary team involving both the academic and private sectors with the mission to accelerate the development of a stem cell-based approach for the treatment of focal cartilage defects and to bring such a therapy to the clinic within 5 years. The PI has included within the proposed team, partners from industry who bring expertise/products relevant to the ultimate clinical aim of cartilage regeneration. Reviewers concurred that the proposal concerns a clinically important research target, and that stem-cell based therapies could offer an advantage over the current treatment of microfracture, since cells could be employed early in the disease process using minimally invasive surgical procedures. A strength of the proposal is that the PI recognizes that simply implanting stem cells does not result in the generation of cartilage with the desired properties, but rather necessitates strategies that promote chondrocyte differentiation and maintenance of their synthetic state in addition to the use of appropriate scaffolds. All reviewers noted that the expertise in chondrocyte biology will be combined with that of several companies that have specialized matrix/polymers that function as scaffolds for cartilage. The most promising combinations of cells and scaffolds will be used in preclinical large animal studies. One weakness of the proposed concept was noted by reviewers. The possibility of cartilage being an immune privileged tissue is mentioned but not discussed or tested. This was raised as a concern since many arthritis conditions have an inflammatory component and lymphocytic infiltrates. Reviewers were divided regarding the goal of bringing the stem cell based therapy for cartilage regeneration to the clinic within the 5 year time frame. One reviewer felt that the timeline is certainly ambitious but not unrealistic in view of the experience of the PI in cartilage biology, and the breadth and depth of expertise and the collaborative environment available at the host institution. One reviewer with an opposing view pointed out that planning to test both human embryonic stem cells (hESCs) and human mesenchymal stem cells (hMSCs) to identify the candidate cell population and the fact that the plan did not include a scaffold development phase made the timeline unrealistic. All reviewers felt that the PI was highly qualified to lead the potential planning and team. The PI is a well established investigator with considerable experience in the biology of cartilage. As founder and director of an industry research center, the PI is very well positioned to establish the necessary collaborations and partnerships involving academic centers and the private sector that will be required for the current project. The PI has three active NIH grants on intervertebral disc repair and hMSC differentiation. The planning approach is well conceived. Workshops are to be organized to promote and ensure a collaborative environment. The team crosses several departments and includes mesenchymal stem cell and cartilage biologists, joint replacement surgeons, molecular biologists, imaging experts, animal surgery experts and a project management expert. Several areas that must be addressed to succeed have been identified and will be the subject of workshops during the planning stage. Members from several local companies with expertise in cell processing and product regulation are identified. A plan is in place to facilitate intellectual property agreements. The enlistment of a collaborator from a neighboring institution to develop an organizational structure is particularly noteworthy and laudable. In summary, the group has diverse expertise and may be able to put together an appealing Disease Team for Arthritis. Reviewer Synopsis Osteoarthritis is a considerable cause of morbidity world wide and a major economic burden to the health care system. A stem cell based therapy is envisioned to provide improved outcome over existing therapies since cells could be employed early in the disease process using minimally invasive surgical procedures. There is recognition of the fact that simply implanting stem cells does not result in the generation of cartilage with the desired properties but necessitates strategies that promote chondrocyte differentiation and maintenance of their synthetic state in addition to the use of appropriate scaffolds to facilitate transplantation, retention and integration of the cells at the site. Accordingly the PI, Dr. Charles Lotz proposes to establish a diverse multidisciplinary team involving both the academic and private sectors with the mission to accelerate the development of a stem cell based approach for the treatment of focal cartilage defects with the mission to bring such a therapy to the clinic within 5 years. The PI has included within his proposed team, partners from industry who bring expertise/products relevant to the ultimate clinical aim of cartilage regeneration. Reviewer One Comments Concept: Arthritis is a common ailment that leads to joint replacement. For sports injuries or trauma-induced focal cartilage defects, treatment is usually by microfracture. However, the premise here is that a stem cell based therapy to repair focal cartilage defects will be a great improvement. Both hES cells and mesenchymal stem cells (MSC) expand and can differentiate into chondrocytes that secrete the appropriate matrix and are said to secret other molecules that promote tissue healing, but a protocol for preconditioning stem cells to direct and maintain their chondrogenic differentiation and synthesis of the matrix of articular cartilage is necessary. This expertise will be combined with that of several companies that have specialized matrix/polymers that function as scaffolds for cartilage. The most promising combinations will be used in preclinical large animal studies. It is surprising that the possibility of cartilage being an immune privileged tissue is mentioned but not discussed or tested. Cartilage is avascular, but much arthritis has an inflammatory component and lymphocytic infiltrates; xenografts of porcine cartilage were rejected. Principal Investigator: Dr. Lotz received his PhD in Medical Engineering at MIT/Harvard Science and Technology program. He is presently Professor and Director (since 2002) of the Orthopedic Bioengineering Laboratory at UCSF, on the executive committee of the Joint Bioengineering Graduate Group of UCSF and UC Berkley. He is a member of NIH Musculoskeletal Tissue Engineering Study Section and has won several awards for spinal research. He is well funded by NIH with two grants on mesenchymal stem cells and repair. Planning Approach: The Executive team crosses several UC faculties and includes mesenchymal stem cell and cartilage biologists, joint replace surgeons, molecular biologists, imaging experts, animal surgery experts and project management expert. Several areas that must be addressed to succeed (manufacturing processes, product regulation, intellectual property management, cell scaffold compatibility, clinical protocols and commercial strategies) have been identified and will be the subject to workshops during the planning stage. Members from several local companies with expertise in processing and product regulation are identified. The UCSF Office of Technology Management will facilitate intellectual property agreements. While time line for the actual Disease Team Award is given already, little is mentioned about how the gaps will be identified and remedied. The group has diverse expertise and may be able to put together an appealing Disease Team for Arthritis. Reviewer Two Comments Concept: • Concept: To repair arthritic cartilage using hMSCs and hESCs combining non-cellular scaffold technologies currently being tested in human clinical trials for industry team members. • Evidence / maturity of the concept: The maturity and feasibility is not fully established. Using both hMSCs and hESCs as possible cell source unnecessarily complicated the project, given the tight timeline of 1.5 years for evaluating the suitability of cell source. The discussion on scaffolds does not provide convincing evidence that these scaffolds will be suitable for hESC or hMSC culture or implantation. It is not clear which scaffolds will be selected for the study either; the planned Disease Team Award does not have a scaffold development phase. Without either one of the two components being defined, the timeline (with GMP phase planned for Years 3 to 4) seems overly ambitious. • Significance: The proposed concept addresses a critical medical problem for treating arthritic patients. A stem-cell based treatment concept is clearly justified. Principal Investigator: The PI has an outstanding track record in basic research and translational research. He has three active NIH grants on intervertebral disc repair and hMSC differentiation. The PI has experience facilitating collaborations among clinicians, scientists and industry. He has assembled a large team to work on this proposed project. Planning Approach: • The team and infrastructure is superb. The collaboration with UCSF Clinical and Translational Science Institute, industry partners, and Technology Transfer Office is a plus. • Although effort has been made to recruit an organizational manager, the interaction among team members and organizational arrangement remain unclear. • A tight and aggressive timeline is given. However details on team interactions and collaboration to develop the Disease Team Award proposal during the planning phase are not discussed. Reviewer Three Comments Concept: Arthritis is an increasing area of unmet medical need. Cartilage replacement has been a target for a number of biotechnology companies in the past and the fact that a successful product has not eventuated in no way detracts from the importance or plausibility of cartilage replacement as a therapeutic target. The degree of difficulty of replacing damaged articular cartilage is perhaps unappreciated. It is as much a cell biological problem as a bioengineering problem and consequently requires a broad multidisciplinary approach of the scope proposed by the PI. The consortium assembled by the PI brings a collective wealth of expertise, know how and experience to the problem at hand. The goal of bringing a stem cell based therapy for cartilage regeneration to the clinic in 4 years is certainly ambitious but not unrealistic in view of the experience of the PI in the cartilage biology area and the breadth and depth of expertise and the collaborative environment available at the UCSF Cartilage Repair & Regeneration Center. Principal Investigator: The PI Dr. Lotz is a well established investigator with considerable experience in the biology of cartilage. In his role as founder and Director of the Orthopedic Surgery Industry Research Center, he plays a role in facilitating collaborations between clinicians, basic researchers and the private sector with the aim of developing novel clinical treatments. He is thus very well positioned to establish the necessary collaborations and partnerships involving academic centers and the private sector that will be required for the current project. Planning Approach: The planning approach is well conceived. Specific areas that need to be addressed (such as IP management across centers; clinical protocols, etc.) have been identified. Workshops are to be organized to promote and ensure a collaborative environment. The enlistment of Dr. Chemers from UC Santa Cruz to develop an organizational structure is particularly noteworthy and laudable.
Conflicts: 

© 2013 California Institute for Regenerative Medicine