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.
In Aim 1, we will test whether stem cells can improve the healing of cartilage after surgery.
In Aim 2, we will find out if stem cells can improve the function of the cells in diseased cartilage.
In Aim 3, we will find out if arthritic cartilage can signal stem cells to migrate into the diseased tissue and start repairing the tissue.
Stem cells fight disease and repair tissues in the body. If this is true, we anticipate that stem cells implanted in arthritic cartilage may also 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 new ways to treat cartilage with or without stem cells. Treating cartilage degeneration would have a positive 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 capital of the world. The recent debate over the moral and the ethical issues of stem cell research have slowed 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 of funding innovative and untested research. The proposal will generate highly innovative results in the treatment of cartilage degeneration and osteoarthritis and will explore the potential use of tissue-engineered products from stem cells. At a minimum, new insight into the role of stem cells as anti-arthritic agents will be gained. 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.
The focus of the proposal, submitted by an orthopedist physician-scientist, is on uses of stem cells for the important clinical problem of arthritis and related diseases. The applicant will test stem cell therapy for damaged cartilage in an in vitro grafting system bathed with stem cells (Aim 1) or bathed in conditioned medium from the stem cells (Aim 2). Aim 3 shifts to regeneration from the secreted product effects of stem cells, examining whether human embryonic stem cell (hESC)-derived mesenchymal stem cells (MSC) can differentiate into cells that home to and repopulate degenerating tissue. These migration assays employ a 2-chamber system so that hESCs can be tracked moving from one chamber to a second chamber containing osteoarthritic cartilage explants. This work, especially the last aim, has significant clinical implications for cell-based therapy.
A major strength of the research is that it is directed at an important clinical problem, arthritis, for which only symptomatic therapies are currently available. Aims 1 and 2 focus on the ways in which stem cells can augment normal repair processes, including a study of extracellular matrix elaboration and turnover, in an in vitro disease environment. The data using muscle cells as a control for the planned hESC-based stem cell studies were considered strong, and Aim 1 was deemed well-designed. The choice of markers to determine whether the cells have arthritic effect were carefully considered and planned. Another strength was planned use of hESCs that were not grown on feeder layers, a design which helps overcome some translational roadblocks for moving the research into humans. Aim 3 will determine the recruitment of MSC by diseased, arthritic cartilage, and this is a timely aim as the mechanism of recruitment of stem cells to sites of injury/degeneration is poorly characterized. Thus these migration assays may help resolve some of the controversies surrounding recruitment and homing of MSC which have applicability beyond arthritis applications. Reviewers considered this to be an elegant proposal with an enormous potential to translate into a therapy. The experiments proposed are clear, and the preliminary data add to confidence that this work can be applied clinically in a relatively short period of time. The applicant’s combined clinical training (knowledge of arthritis and cartilage) and basic science educational preparation were important strengths of the application.
Reviewers were disappointed that the entire scope of the planned research was to be conducted only in vitro. Reviewers considered this a negative, as the preliminary in vitro data suggest that the applicant should proceed quickly to in vivo studies, especially since the applicant has extensive clinical (in vivo) experience. Thus the research plan was considered overly cautious. The reviewers felt that insufficient attention to trouble-shooting and alternative plans was presented in the grant, raising concern for the qualifications of the applicant to conduct the research, especially as his mentoring plan was fairly generic (“meetings, lectures”). Reviewers all raised concerns that the presentation of differentiation data was confused in terms of attribution. The presentation made it sound as if these data were not generated by the applicant, unlike data presentation in other parts of the proposal. There was no plan offered for derivation of the progenitor cells from hESC. Since the publication record of the applicant does not show command of stem cell biology, these data added to concern about an insufficient background in stem cell biology. Furthermore, the application did not readily outline the division of labor or describe who would actually carry out the experiments.
The applicant attended medical school training in India, receiving an MD in 1982, finishing an orthopedics residency in 1987. In 1996 the applicant joined the biomechanics lab at his/her institution, and is now director of that departmental core lab, and is involved in the training of clinical fellows. The applicant is an experienced orthopedic surgeon. The applicant received a PhD in bioengineering from a top program just last year, and basic science work from this time recently won an award from the International Cartilage Research Society. One concern was the relative lack of demonstrated stem cell experience: despite two years in a prestigious California stem cell lab, no publications resulted from that time. The applicant’s publications (18) are largely clinical, and the applicant has received three small (non-NIH) grants. This track record was considered good, and the potential for the applicant to be a leader in the orthopedics research community was considered high. Given the difficulty of orthopedics departments to support research, this proposed work was felt to be very important for the field.
The institution provides the applicant with 2000 sq ft of space but it is unclear how this is supported (departmental space?), and how much of this space is devoted to the planned research vs. the core lab activities. Despite a very strong letter of career support from the clinical department chair, it is a concern that there is no mention of protected research time away from clinical duties, as the applicant has patient care duties, is committed to training fellows in orthopedics, and runs the core lab. The mentors are all appropriate and qualified for the project, and are well positioned to help guarantee the success of the research.