Year 3

Our Disease Team is focused 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 that can continuously make immune cells is the only established cure for SCID. Unfortunately, the current ways of performing these transplantations are imperfect, so that some 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 must undergo treatments to eliminate their own blood forming stem cells so that healthy donor stem cells will take and grow. The only available methods to accomplish this elimination of stem cells are toxic chemotherapies or radiation that have side effects which develop shortly after transplant or after many years. These negative side effects include, but are not limited to, injury to the liver, delays in development and negative effects on the brain. Because chemotherapy is toxic, some SCID patients are infused with donor cells and no attempt is made to eliminate their own stem cells. In those cases, the children survive with immune function, but they do not engraft with true blood stem cells. Hence, their immune function is often suboptimal. 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 the worse case scenario the child dies as a result of the toxicities associated with the transplant procedure.

Our Team is focused on the elimination of these transplant complications. To address the problem of toxic therapies needed to make space for donor cells, we are testing a biologic reagent to replace the chemotherapy/radiation. This biologic agent is an antibody that recognizes a molecule called CD117. CD117 is present on the surface of blood forming stem cells. In rodent studies we observed that treatment 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 humans that specifically target and deplete the blood forming stem cells.

To eliminate the problem of graft-vs-host disease, we set out to produce two other antibodies, called anti-CD34 and anti-CD90. These antibodies label human blood forming stem cells and allow us to separate the stem cells from harmful T cells. Blood forming stem cells are a rare population comprising only one in several thousands of cells in a standard graft.

In the first year of this award we successfully produced anti-CD34 and anti-CD90 antibodies. In this second year we completed the studies that show we can use these antibodies to reproducibly purify blood stem cells for infusion into patients. We also completed the studies in a large animal model necessary for us to test the anti-CD117 antibody in patients. This past year we were successful in our filing of an Investigational New Drug Application (IND) with the Food and Drug Administration (FDA). Our clinical study has been allowed to proceed. In August 2016 we opened the clinical study for enrollment.

We are excited to begin our studies to treat children with SCID. These children are highly sensitive to the negative effects of chemotherapy, and because they have no immune system to reject donor cells, treatment of these patients with the anti-CD117 antibody alone should allow the purified blood stem cells to take. The implications of this study are broad. If successful, our study will open the door to a transplant approach in which a non-toxic agent is used to prepare recipients to accept blood stem cell grafts that do not cause graft-vs-host disease. There are tens of thousands of patients with other diseases that can benefit from this new way of performing transplants, including those with those with sickle cell anemia, thalassemia, and autoimmune diseases such as childhood diabetes, multiple sclerosis, and lupus erythematosus. We believe we are well on our way to changing the future of blood stem cell therapy.