Disease Team Therapy Planning I
Osteoarthritis (OA) is one of the most serious of the degenerative diseases. It afflicts up to 70% of individuals over 65 years of age (21 million Americans). The lack of an innate capacity for regeneration and repair of the cartilage cells in our joints is the primary cause for the disease, and the reason it worsens with age. Since merely taking pain medications or having invasive joint replacement surgery, where the ends of the bones in our joints are replaced with plastic and metal prosthetic joints, is not considered ideal solutions to this medical problem, scientists have long sought for a means of introducing into the joint, young healthy cells that would be capable of doing what our joint cannot do on its own; namely, repairing the damage. Historically, such cell-based therapies have taken two forms. In one approach, cartilage cells are surgically removed from the joint and placed in culture to allow the cells to proliferate into a greater number of cells. These are then returned to the same patient’s joint in the hope that they will participate in repair. In another strategy, cells from the patient’s bone marrow, are similarly removed, expanded in number in the lab, and returned to the diseased joint. In both cases, these cells show minimal benefit to the patient, in part because the growth of the cells outside the body changes them such that they are no longer effective in repairing the damaged joint. Human embryonic stem (hES) cells have the potential to become virtually any cell type in the body. Therefore, hES cells may offer an exciting opportunity to manufacture many cell types previously unavailable to medical researchers, including cells that could be used to effectively repair the joint in ways never observed in the past. We examined >140 novel cell types generated from hES cells and tested them for their ability to make definitive cartilage. One of these cell types showed markers suggesting that it had properties different from the previously tested cell types that may allow it for the first time to robustly regenerate the joint. When the line was combined with a matrix of molecules called “HyStem” to help the cells adhere to the joint tissue, this combination product showed a marked regeneration of the joint in a rat model of osteoarthritis. This proposal seeks funding of research and development to thoroughly test this new technology prior to administration in humans. It is anticipated that the resulting research could allow the first human clinical trials of this first-in-class therapy within four years. In summary, the successful completion of this research and development has the potential to introduce a new type of therapy for a leading degenerative disease, a disease that is the leading complaint of an aging population.
Statement of Benefit to California:
According to the U.S. Census Bureau, “a substantial increase in the number of older people will occur during the 2010 to 2030 period, after the first Baby Boomers turn 65 in 2011. The older population in 2030 is projected to be twice as large as in 2000, growing from 35 million to 72 million and representing nearly 20 percent of the total U.S. population at the latter date”. This same dramatic rise in the number of older people is occurring in the State of California. It is expected to bring with it a tsunami of health care costs that the State simply cannot afford. The leading complaint of an aging population is the pain associated with age-related osteoarthritis (OA). OA afflicts up to 70% of individuals over 65 years of age (21 million Americans) and afflicts women more frequently than men. Not only does it cause pain, but it also leads to disability. Family members and health care providers are required help with basic services, thereby reducing the economic productivity of the people of California and increasing the cost of patient care. OA is caused by a progressive loss of cartilage on the surfaces of the bones in our joints. Since the cartilage cells have essentially no capacity to regenerate, the stresses of age lead to a progressive loss of the cells, and eventually the bare bone beneath the cartilage begins to be exposed, with the result that movement in the joints is extremely painful. As of today, there is no cure for the disease. Instead, therapeutic alternatives are largely medications to reduce pain and inflammation, or the expensive surgical replacement of the joint with artificial surfaces made of metal and plastic. The technologies described in this proposal are intended to allow for the first time a means of biological joint replacement. Using human embryonic stem cells, that are capable of forming all the cell types in the human body, new cells have been isolated that may have the potential to regenerate the cartilage in the joints of patients with OA, thereby decreasing the need for expensive surgical alternatives and allowing those afflicted with the disease to regain mobility and independence which would decrease the costs of dependence on family members or health care providers for daily needs. In summary, the new stem cell-based technologies described in this proposal have the potential to regenerate the tissues in joints of people afflicted with OA, the leading complaint of an aging Californian population, reduce suffering and replace current therapies with a less costly and invasive solution and reduce the costs associated with managing this difficult disease.
EXECUTIVE SUMMARY Project Synopsis This proposal aims to treat damaged joints affected by osteoarthritis (OA) using an embryonic stem cell (ESC)-derived product that can regenerate cartilage. The applicant proposes to combine ESC-derived cartilage-producing cells (chondrocytes) with a biocompatible polymer, called HyStem, to treat damaged cartilage associated with osteoarthritis in joints, especially the knee or hip. They are seeking to develop an off-the-shelf product that will be injected into the joint through a minimally invasive procedure to promote cartilage repair. The study objective is to complete IND-enabling studies and file an IND within the four-year timeframe of the project. Significance and Impact - Current therapies have limited durability. If effective, this could offer a more a permanent replacement of the cartilage, which would significantly improve the care of OA patients. The proposed injectable therapy would be highly competitive against currently available surgical techniques. Project Rationale and Feasibility - Reviewers were not convinced from the data presented that the cells are true functioning chondrocytes. Reviewers cited a number of flaws in the supporting data; for example, the marker that was used for chondrocytes is not accepted as a definitive marker. Reviewers were also not convinced from the data presented that the proposed cells are superior to mesenchymal stem cells, which are being developed as an alternative approach. - Reviewers expressed concern about the development readiness of the proposed therapy. The chosen cell line has not been screened for defects in cartilage-related genes that might adversely affect the therapy, suggesting that a single development candidate may not yet have been identified and raising the possibility that much of the work may need to be repeated. - Most of the toxicology studies performed were not conducted using either the final intended cell line or the intended cell culture system. - Several reviewers disagreed with the assertion that the knee is an immune-privileged site, raising the possibility of an immune response to the proposed treatment in what will be an already inflamed joint. - The ability to repopulate and repair a large lesion, as is seen in OA, will be a major challenge. Principal Investigator (PI) and Planning Leader -The PI will both lead the project and serve as planning leader. The PI has significant expertise in translational research and development as well as in project management and has the leadership and experience to move this product into the clinic. -Strong team of experts has been assembled to evaluate the clinical development plan