Musculoskeletal Tissue Regeneration
All adult tissues contain stem cells. Some tissues, like bone marrow and skin, harbor more adult stem cells and other tissues, like muscle, have fewer. When a tissue or organ is injured these stem cells possess a remarkable ability to divide and multiply. In the end, the ability of a tissue to repair itself seems to depend on how many stem cells reside in a particular tissue, and the state of those stem cells. For example, stress, disease, and aging all diminish the capacity of adult stem cells to self-renew and to proliferate, which in turn hinders tissue regeneration.
Our strategy is to commandeer the molecular machinery responsible for adult stem cell self-renewal and proliferation and by doing so, stimulate the endogenous program of tissue regeneration. This approach takes advantage of the solution that Nature itself developed for repairing damaged or diseased tissues, and controls adult stem cell proliferation in a localized, highly controlled fashion. This strategy circumvents the immunological, medical, and ethical hurdles that exist when exogenous stem cells are introduced into a human. When utilizing this strategy the goal of reaching clinical trials in human patients within 5 years becomes realistic.
Specifically, we will target the growing problem of musculoskeletal diseases by local delivery of a protein that promotes the body’s inherent ability to repair and regenerate tissues. We have evidence that this class of proteins, when delivered locally to an injury site, are able to stimulate adult stem cells to grow and repair/replace the deficient tissue. We have developed technologies to package the protein in a specialized manner that preserves its biological activity but simultaneously restricts its diffusion to unintended regions of the body. For example, when we treat a skeletal injury with this packaged protein we augment the natural ability to heal bone by 350%. This remarkable capacity to augment tissue healing is not limited to bones: the same powerful effect can be elicited in muscle, heart, and skin injuries.
The disease target, musculoskeletal impairments, represents an enormous health care burden that is expected to escalate with time. As California’s population ages, the cost to treat chronic diseases such as osteoporosis and arthritis will skyrocket. Thus, our proposal addresses a present and ongoing challenge to healthcare for the majority of Californians, with a novel therapeutic strategy that mimics the body’s inherent repair mechanisms. Our scientific strategy has been rigorously validated and is mature; reagents are available to our group; and the interdisciplinary research team has the necessary expertise to bring these fundamental findings from the bench to the bedside in a 5 year time frame.
Musculoskeletal disease poses a significant biomedical burden on the United States Healthcare system at an estimated $240 billion annually. Symptoms of musculoskeletal disease are the number two most cited reasons for visit to a physician. In 2003, musculoskeletal disease accounted for 157 million visits to physicians’ offices, 15 million visits to hospital outpatient departments, and 19 million visits to emergency departments. As such, musculoskeletal disease is the leading cause of work-related and physical disability in the United States, with arthritis being the leading chronic condition reported by the elderly. In adults over the age of 70, 40% suffer from osteoarthritis of the knee and of these nearly 80% have limitation of movement. By 2030, nearly 67 million US adults will be diagnosed with arthritis.
In California alone, trends for musculoskeletal disease parallel those that are seen nationwide. In the last decade, the number of people suffering from osteoarthritis has been increasing steadily. In 2005, this number reached nearly one quarter of a million individuals that required hospitalization due to the severity of their condition. In the same year, nearly 200,000 individuals required hospitalization for back problems and vertebral disease. The State of California also reported over half a million more cases in 2005 requiring hospitalizations for reasons such as infective arthritis/osteomyelitis, traumatic joint disease and fractures, and autoimmune diseases of the skeleton. In aggregate, the State of California reported an average length of stay for these hospitalizations to be approximately 5 days, totaling up to over 5 million sick days from patients requiring hospitalization due to musculoskeletal disease alone each year. Furthermore, the State of California reports that each inpatient stay in these cases averages approximately $50,000 in direct hospital charges. This overwhelming statistic brings the total estimated socioeconomic burden (direct charges alone) posed by musculoskeletal disease to over $50 billion annually. This is a staggering biomedical burden on California’s economy.
The treatment of musculoskeletal diseases uses a lion’s share of our healthcare dollars: in 2003, 652,000 total joint replacement procedures were performed in the US and estimates are that by 2030, the number of total knee replacements will increase by 673%—reaching 3.48 million. In 2005 alone, over one million Californians were discharged from inpatient stays at hospitals with multiple, specific diagnoses related to musculoskeletal disease. The vast majority of these cases were reported for individuals between 45 and 84 years of age. The biomedical burden of musculoskeletal diseases for the state of California is enormous and our goal is to devise strategies that enhance bone regeneration. This strategy is equally relevant to skeletal injuries and to diseases characterized by bone loss, such as osteoarthritis and osteoporosis.