Year 1

The focus of our Disease Team is on the treatment of a lethal genetic disease in children called severe combined immunodeficiency (SCID) also known as the “bubble boy” disease. Children with SCID are born without a functional immune system and therefore are extraordinarily vulnerable to serious infections. If untreated, most of these children die by the age of two. Transplantation of blood forming stem cells is the only established cure for SCID. Unfortunately, the current ways of performing these transplantations is imperfect, so that a percent of the transplants fail. There are two major problems that are encountered in the procedure that reduces the success of the transplants. The first problem occurs because the children undergo treatments to eliminate their own blood forming stem cells so that they will accept the stem cells of healthy donors. The methods available to accomplish this stem cell depletion are toxic chemotherapies that have side effects that develop shortly after transplant or after many years. These negative side effects include, but are not limited to toxicity to the liver, delays in development and effects on the brain. Because such treatments are toxic, some children are infused with donor cells without stem cell depletion. In those cases, a percentage have relatively poor immune function. The second problem develops as a result of the cell content of the donor grafts that contain the blood forming stem cells. Healthy donor grafts contain not only the life-saving stem cells but have contaminating cells (T cells) that have the potential to attack and destroy some of the tissues in the transplanted patients. Attack of recipient tissues by donor T cells is a syndrome called graft-vs-host disease. In worse case scenario the child dies as a result of the toxicities associated with the transplant procedure.

Our Team aims to eliminate these complications of transplantation. To address the problem of toxic therapies needed to make space for donor cells, our approach is to replace these regimens with a biologic reagent. The biologic agent we are testing is an antibody that recognizes a molecule called CD117. CD117 is present on the surface of blood forming stem cells. In rodent studies we have observed that targeting blood forming stem cells with an anti-CD117 antibody safely depletes recipient cells, thereby allowing the donor stem cells to engraft. There is no other biologic agent available for human use that can specifically deplete the blood forming stem cells. In the last year, we continued the development of an anti-CD117 antibody that binds human cells. We made the exciting observation that in large animals that express CD117 molecules similar to humans, the intravenous administration of the anti-CD117 antibody results in rapid depletion of blood forming stem cells, similar to what we have observed in mice. The depletion of stem cells is transient since the animals recover their stem cells after a few weeks. But the effect appears to be long enough that transplanted donor cells will have a chance to takeover.

To eliminate the problem of graft-vs-host disease, we have simultaneously produced two other antibodies, called anti-CD34 and anti-CD90. These antibodies label human blood forming stem cells and allow the stem cells to be separated from other potentially harmful cells including T cells. Blood forming stem cells are a rare population comprising only one in several thousands of cells in a standard graft. In the last year we have successfully produced anti-CD34 and anti-CD90 suitable for use to purify stem cells from human grafts. In pilot studies, we have been able to produce purify stem cells away from the other graft cells so that they comprise >97% of the infused product.

Our progress this year, demonstrates that we are well on our way to the initiation of our proposed clinical trial for the treatment of SCID. Children with SCID were chosen as the target population because they are highly sensitive to the negative effects of chemotherapy and, given our existing knoweldge of transplants in these patients, they are the patient group that will allow us to most clearly measure the effect of the anti-CD117 antibody. However, the implications of our study are broad. The tens of thousands of other patients that are cured by blood forming stem cell transplantation each year have the same two potential complications as children with SCID – toxicity from the regimens they need for the donor cells to take, and the possibility of graft-vs-host disease. Transplant patients include those with incurable cancers, sickle anemia, thalassemia, and many others. Blood forming stem cell transplantation can also be curative for autoimmune diseases such as childhood diabetes, multiple sclerosis, and lupus erythematosus. Thus, success in our study will open the door for the use of this approach by markedly improving the way this important form of stem cell therapy is done in the future.