The proposed research will directly contribute to the development of related and unrelated donor umbilical cord blood stem cell transplantation (CBT) as a curative stem cell therapy with potentially acceptable benefit-risk ratio for patients suffering from the myriad of severe forms of autoimmune diseases (AD) for which no satisfactory treatment is currently available. These diseases include but are not limited to scleroderma, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, Crohn's disease, ulcerative colitis, type I diabetes mellitus, juvenile idiopathic arthritis, dermatomyositis, mixed connective tissue disease, Behcet, ankylosing spondylosis, Sjogren's syndrome and psoriasis. The proposal will demonstrate the feasibility of this approach in achieving a permanent cure for patients with AD, and assess the benefit-risk or survival-mortality ratio of this approach.
CBT is the latest form of stem cell transplantation which first gained proof of concept in a Fanconi's Anemia patient in 1998 (Gluckman et al. NEJM). Since then, it is estimated that over 10,000 such transplants have been performed worldwide for patients with both malignant and non-malignant disorders. Like other stem cell transplantation (SCT) such as bone marrow or peripheral blood transplantation, unrelated or related donor CBT can theoretically achieve a cure for AD patients by removing the offending autoimmune immune system and replacing it with one that will not attack the host. This approach gained proof of concept when AD patients with diseases such as leukemias achieved complete remission of their AD when SCT was performed for their leukemias. Unlike most approaches to the treatment of AD, SCT treats the underlying cause of the disease and not the symptoms, thus it is able to achieve a cure. Unfortunately, unrelated SCT is a highly risky procedure with an average 1-year mortality is around 53.2% for the 6,265 patients transplanted in the US (NMDP 2005 Transplant Center Directory) and ~40% for non-malignant diseases, which makes the procedure unacceptable for patients. Recently, CBT has made significant advances and shown to achieve outstanding survival in patients with non-malignant indications when high cell doses are used, such as thalassemia (Jaing et al. 2007) and Krabbe's disease (Escolar NEJM 2005 ). By taking a similar high cell dose CBT approach, it is anticipated that superior survival and cure rates may be achieved such that this may be one of the viable options for patients suffering from severe forms of AD.
Statement of Benefit to California:
If successfully carried and with the anticipated results achieved, the proposed research will benefit California and its citizens in numerous ways.
1. Most importantly, California patients with autoimmune diseases will benefit from the availability of a curative stem cell therapy option. These diseases include scleroderma, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, Crohn's disease, ulcerative colitis, type I diabetes mellitus, juvenile idiopathic arthritis, dermatomyositis, mixed connective tissue disease, Behcet, ankylosing spondylosis, Sjogren's syndrome, psoriasis etc... Currently, there are no good treatment options for many of these patients, especially the ones with severe forms of these diseases. A curative option will extend their survival significantly
2. These diseases impact adversely on the quality of life of these patients and their families. A cure will greatly improve their quality of life.
3. Severe chronic diseases such as autoimmune diseases exact a heavy financial burden on society in numerous ways. These debilitating theses costs billions of dollars each year on the economy of the State in terms of medical costs and lost productivity. A curative option will save billions of dollars for California and greatly improve the productivity and lives of these patients and their families.
4. Obviously, the clinical benefit of a cure for autoimmune diseases does not stop at the borders of California, but will extend to patients around the world, which will enhance California's reputation as an entrepreneurial developer and pioneer of stem cell therapy. This will help California attract and retain talented stem cell researchers and scientists to work in the academic or industry sectors of the State.
5. Currently, thousands of cord blood transplants are performed annually with an outstanding safety and efficacy record, which means that this is an approach that can be translated clinically and commercially in a few years, relatively quickly compared to many of the other stem cell therapies that are proposed. It is important to note that patients with autoimmune diseases can be transplanted today at numerous centers around the world.
6. Moreover, since the project principal investigator has already achieved proof of concept in an autoimmune disease patient using the approaches outlined in this proposal and has used similar approaches to demonstrate superior patient survival in other non-malignant disease models, this project has excellent probability in demonstrating feasibility and achieving acceptable benefit-risk ratio.
7. Since most of the funding for CIRM appear to be earmarked for embryonic stem cell research, funding of projects involving non-embryonic stem cells, such as cord blood, will be help achieve a balanced approach to funding stem cell research.
8. This proposal will create quality jobs for California stem cell transplant centers and companies.