General Interests

    Sequence differences in an individual’s genomic DNA are part of what underlies the great variation in humans. In general, these differences give robustness to our species’ ability to adapt to new situations, and these differences are known as “polymorphisms.” Certain polymorphisms can be protective against disease. For example, people who have a polymorphism called CCR5delta32 seem to be relatively resistant in developing AIDS after infection by the HIV virus. Other polymorphisms can be protective against disease in certain circumstances or can cause disease in other circumstances. Finally, there are certain polymorphisms that almost always cause disease—these polymorphisms are often referred to as “mutations.” Diseases that are caused by a mutation in a single gene are called “monogenic diseases.” Diseases such as cystic fibrosis, severe combined immunodeficiency, hemophilia, and sickle cell disease are examples of monogenic diseases but we now know of over 6000 different monogenic diseases that represent one in two hundred live births. We are interested in developing therapy for monogenic diseases using gene therapy. In particular, our focus is on how to “correct” mutations that cause disease. Our lab is particularly interested in trying to correct the mutations that cause sickle cell disease and severe combined immunodeficiency (“bubble-boy” disease). We believe, however, that if we can find a way to treat these two diseases, that the method would be generally applicable to the other 6000 monogenic diseases and perhaps to non-monogenic diseases as well. While our work is focused on ways of correcting mutations that cause disease without changing any other aspect of the DNA, almost certainly this approach will require the use of stem cells. We believe that “gene correction” is most likely to succeed if we can correct the mutation in the patients’ stem cells in the laboratory, give back those corrected

stem cells to the patient and have those corrected cells re-populate the body, thereby curing the disease. Obviously, stem cells are a central and critical aspect of this vision and we support stem cell research in a broad way so that one day this vision may actually become a reality. Currently, our research is still laboratory based and we have no clinical trials for this type of therapy; we are also not aware of any ongoing clinical trials based on gene correction. However, we hope that in the next several years we will be in a position to start conducting preliminary clinical trials for gene correction type gene therapy.

Brief Description of Sickle Cell Disease

    Sickle cell disease is an inherited autosomal recessive disease caused by a single change in the beta-globin gene. It was the first disease for which the DNA defect was identified (30 years ago) and is caused by a base change in DNA from adenine (A) to thymidine (T) causing an amino acid change from glutamine to valine. When a person has sickle cell trait (one copy of the sickle gene), the person usually has no symptoms. In fact, people who have sickle cell trait are protected against severe forms of malaria. Thus, the sickle change is really a polymorphism that can actually protect from disease in certain circumstances, such as in a setting where malaria is prevalent. However, if a person has two copies of the sickle gene then they almost always develop sickle cell disease. Red blood cells carry oxygen to the tissues of the body so that they can work correctly. In order to most efficiently deliver oxygen to the tissues, red blood cells have to squeeze through small capillaries to unload oxygen. Normal red blood cells are able to deform and squeeze through those capillaries. In sickle cell disease, red blood cells deliver oxygen just fine but occasionally after unloading oxygen, the globin protein in the cell polymerizes to form a stiff, rod-like structure—sometimes adopting a “sickle” shape. When globin does this, the red cell cannot deform properly to get through the small blood vessels. If enough sickle red blood cells lose the ability to deform at the same site, it can cause a blockage of the blood vessel and oxygen can no longer be efficiently delivered to the tissue. Depending on where the blockage occurs, it can cause different problems. If the blockage occurs in the brain, it can cause a stroke; if it occurs in the lungs, it can cause a severe respiratory problem called acute chest syndrome; if it occurs in the bone, it can cause a severe painful episode. . . What we hope to do someday is to be able to remove the blood stem cells (hematopoietic stem cells) from a patient with sickle cell disease and then change the adenine (A) back to a thymidine (T) in either one or both copies of the beta-globin gene in the laboratory. We would then re-infuse the “corrected” stem cells back into the patient. Hopefully, the corrected stem cells would repopulate enough of the blood system to prevent the development of blockages that cause sickle cell disease.