Abstract
A promising approach for the treatment of genetic diseases is called gene therapy. Gene
therapy is a relatively new field of medicine in which genetic material (mostly DNA) in the
patient is changed to treat his or her own disease. In gene therapy, we introduce new genetic
material in order to fix or replace the patient's disease gene, with the goal of curing the
disease. The procedure is similar to a bone marrow transplant, in that the patient's
malfunctioning blood stem cells are reduced or eliminated using chemotherapy, but it is
different because instead of using a different person's (donor) blood stem cells for the
transplant, the patient's own blood stem cells are given back after the new genetic material
has been introduced into those cells. This approach has the advantage of eliminating any risk
of graft versus host disease (GVHD), reducing the risk of graft rejection, and may also allow
less chemotherapy to be utilized for the conditioning portion of the transplant procedure. To
introduce new genetic material into the patient's own blood stem cells we use a modified
version of a virus (called a 'vector') that efficiently inserts the "correcting" genetic
material into the cells. The vector is a specialized biological medicine that has been
formulated for use in human beings.
Fetal hemoglobin (HbF) is a healthy, non-sickling kind of hemoglobin. The investigators have
discovered a gene that is very important in controlling the amount of HbF. Decreasing the
expression of this gene in sickle cell patients could increase the amount of fetal hemoglobin
while simultaneously reducing the amount of sickle hemoglobin in their blood, specifically
the amount in red blood cells where sickle hemoglobin causes damage to the cell, and
therefore potentially cure or significantly improve the condition. The gene we are targeting
for change in this study that controls the level of fetal hemoglobin is called BCL11A.
In summary, the advantages of a gene therapy approach include: 1) it can be used even if the
patient does not have a matched donor available; 2) it may allow a reduction in the amount of
chemotherapy required to prepare the patient for the transplant; and 3) it will avoid certain
strong medicines often required to prevent and treat GVHD and rejection. Our lab studies with
normal mice, mice that have a form of SCD, and with cells from the bone marrow of SCD
patients who have donated bone marrow for research purposes show this approach is very
effective in reducing the amount of sickle hemoglobin in red cells. Our pilot trial testing
this approach in 10 patients with SCD has shown that the treatment has not caused any
unexpected safety problems, and that it increases HbF within the red blood cells. Our goal is
to continue to test whether this approach is safe, and whether using gene therapy to change
the expression of BCL11A will lead to decreased episodes of vaso-occlusive crisis pain in
people with SCD.
