Seeking a way to make gene therapy work for inherited blood diseases

Anthony Blau

Bone marrow transplantation is a curative treatment for inherited blood disorders such as sickle cell anemia, but it is seldom used for this purpose, according to Dr. C. Anthony Blau, assistant professor of medicine in the Division of Hematology. Why?

“Two reasons,” said Blau, whose work focuses on possible alternatives. “Bone marrow transplantation is toxic, and only a minority of patients have compatible donors.”

Blau is leading a team working on developing techniques to enable gene therapy for a wide range of inherited blood disorders, including sickle cell anemia.

Red blood cells, which normally have a disc shape, are dramatically altered in sickle cell anemia, adopting a crescent-like “sickled” morphology that results in clogging of the circulation and extreme pain. While sickle cell anemia is a disease of red blood cells, permanent correction of this and other genetic blood disorders requires correction at the level of stem cells in the bone marrow.

Stem cells, which last for a lifetime, produce all of the different cell types in the blood, including red blood cells. “The single most formidable obstacle to stem cell gene therapy is the inefficiency of gene delivery into stem cells,” Blau said.

The primary goal is to use a retrovirus to transfer a gene into the stem cell that will correct the mutation. In the best results reported so far, only 1 percent of stem cells incorporated the therapeutic gene, far too low a frequency for therapeutic effects.

Blau estimates that correcting 15 to 20 percent of stem cells, however, would have major therapeutic benefits. “We probably don’t need to correct 100 percent of stem cells,” he says.

Blau, associate program director for gene therapy at UW Medical Center’s Clinical Research Center, will discuss his research in a Science in Medicine Lecture Series presentation, “In Vivo Selection for Gene and Cell Therapy,” on Friday, Nov. 6, from noon to 1 p.m., in room D-209, of the Health Sciences Center.

“Our aim is to directly harness the proliferative machinery of the stem cells,” he said.

The approach is based on the principle that receptors stimulate cell growth when two copies of the receptor protein are brought close to one another. This process, called dimerization, is normally set off in the presence of a specific growth factor.

Blau has created a modified receptor that can be dimerized using a specific drug rather than a growth factor. When the drug is applied to genetically corrected stem cells, it binds with the receptor and sets off signals that stimulate rapid growth. This allows researchers to specifically stimulate stem cell growth only in genetically corrected stem cells.

Ultimately, researchers are working toward setting off these events in an individual with a blood disorder. “If we can show this works in a mouse model, we can move on to testing the therapy in primates. If we are successful there, we would be sufficiently encouraged to proceed into clinical trials,” Blau said.

Researchers are about two to three years away from the first human clinical gene therapy trials for such blood disorders, Blau estimates. “We need to emphasize that these first generation clinical trials are not likely to confer major therapeutic benefits, but they will form the basis for developing treatments that eventually will be effective” he said.

Primary applications of the technology would include treating blood cell diseases such as adenosine deaminase deficiency (the “Bubble Boy” disease), sickle cell anemia and beta-thalassemia, the most common genetic blood disease in the world.

“While all of these diseases can be cured with bone marrow transplantation, this treatment is encumbered by the risk of toxicity and death. To be competitive, gene therapy must provide a more attractive option,” Blau said.

Blau completed a residency in internal medicine at Duke Universiy before joining the UW in 1989 as a senior fellow in the Department of Medicine’s Division of Oncology. He received an M.D. in 1986 from Ohio State University. ¶

Will Morton