Successful stem cell therapy requires the exchange of diseased or non-functional stem cells with healthy ones. These healthy stem cells can come from either a donor or can be stem cells that are modified by gene therapy techniques. One important step in this process of repair and replacement is to eliminate the existing diseased cells so that physical space is created for the healthy ones, and competition for environmental factors that nurture and support the stem cells are removed.
Bone marrow transplantation (BMT) is the oldest and most common form of stem cell-based therapy. Thousands of patients undergo BMT yearly to successfully cure cancers or disorders of blood formation. Bone marrow contains mixtures of cells, but only a minority are the blood forming stem cells. These stem cells are the only cells that can permanently generate new blood for the life of a recipient. In a BMT the stem cells from a donor replaces the recipient’s diseased stem cells. Currently, recipients that undergo BMT are treated with toxic agents such as radiation and chemotherapy in order to in order to eliminate their own blood forming stem cells and permit the donor cells to take and develop.
Our Disease Team will focus on the treatment of a disorder in children called severe combined immune deficiency (SCID). Children with SCID are born without certain types of white blood cells because their own stems do not make these cells, and are highly susceptible to serious infections. If a child with SCID is not treated, it is likely she or he will die by the age of 2 years. BMT is the only established cure for this disease. Unfortunately, the way the transplants are currently performed, with toxic treatments to prepare the children to accept the donor cells and the side effects caused by lymphocytes that contaminate standard blood cell grafts reduces the likelihood of successful cure.
We propose to test a protein called an antibody that recognizes a molecule called CD117 present on blood forming stem cells. This antibody can safely target a recipient’s stem cells making room for the donor cells. When used in mice, this antibody resulted in excellent donor stem cell take and cured mice that had a condition equivalent to human SCID. Our objective is to test the antibody that targets human CD117 to safely prepare children with SCID to accept blood forming stem cells from a donor. Based on the animal studies we expect that this antibody will markedly increase the levels of donor cells as compared to current standards.
By receiving funding from this planning award we have been able to establish a multi-disciplinary team that will allow us to achieve our goals. We have brought together world experts in transplantation, protein development and clinical study design who have the shared objective of bringing the technology of antibody targeting stem cells to patients. We have developed a comprehensive plan for the treatment of SCID patients that we hope in the near future will replace the toxic treatments required to cure this disease.
Success in this study would have impact that extends far beyond a superior treatment for SCID. If the antibody treatment results a stronger blood system originating from a donor in SCID patients, this result would prove that the antibody could be used to optimize engraftment of gene-therapy modified cells and could be applied to the treatment the many other diseases that need a BMT. These diseases include, but are not limited to sickle cell and Fanconi’s anemia, autoimmune diseases like diabetes and multiple sclerosis, and cancers that originate from the blood system such as leukemias and lymphomas.