Tim Townes, PHD, is taking his third big step in a journey that began in 1997. That is the year he made international news by developing the first practical animal model for sickle cell disease. Ten years later, his lab made even bigger headlines when UAB and MIT repeated the first successful treatment of sickle cell anemia in animals. Now the Chair of the UAB Department of Biochemistry and Molecular Genetics is ready to follow up this proof in principle using skin cells and the world’s first Sanyo cell-processing workstation to begin developing this treatment for humans.
“With three master genes, we can switch on the code in a patient’s own skin cells to turn them into induced pluripotent stem cells (iPS). This resets the cells as if they were early embryos with the potential to become any type of tissue,” Townes said. “In some cases, we can correct the defective gene in the skin cell, and in others we do it later. We replace the sickle cell gene with a healthy gene, and then we stimulate the corrected cells to become red blood cells that can be injected back into the body much like a bone marrow transplant.
“The cells migrate straight to the marrow and start producing normal red blood cells. The hardy new cells also have a longer life, so if 10% of the cells in the marrow are corrected, eventually 90% of the red cells in the body should be normal.”
Making room for the corrected cells in the marrow will likely require something like a one-day chemotherapy treatment. But unlike cancer patients, sickle cell patients should only feel the effects of one day of treatment. As their new cells start producing healthy red blood cells, they should feel better for a lifetime.
Using the patient’s own skin cells to produce stem cells should reduce the risk of a negative immune response. Another exciting aspect of this research is that a similar approach should also work to cure or improve treatment of a number of other serious diseases.
“Disorders arising from a single gene error would be obvious targets,” Townes said. “There’s potential in treating tumors and immune disorders. A condition such as diabetes would take a dual approach—first growing new islet cells to transplant, and second correcting T-cells so they didn’t attack the new islet cells.”
Townes says that although only one defective gene causes sickle cell disease, he is also working to detect modifier genes that influence the course of the disease.
“When a treatment is developed and approved, it will still be a while before it’s widely available,” he said. “There are over 70,000 people in the US who have the disorder and millions worldwide. Alabama has one of the largest patient populations.
“We’d like to get treatment to patients who can benefit most from it as soon as possible. To do that, we need to understand which patients are likely to be among the 20% who will experience the worst effects of the disease.”
In a sickle cell crisis, defective blood cells can block whole vessels, causing strokes, destroying kidneys, inflaming painful muscles and joints, and clogging lungs to create the pain of a heart attack that goes on and on.
“When each child is screened for sickle cell disease at birth, if we could also screen for modifier genes, we could identify children likely to have the most devastating effects,” Townes said. “We could correct the problem early before symptoms appear and before damage is done. One treatment would free them of sickle cell for life.”
After beginning the first step to transform human skin cells to iPS cells, Townes hopes to work through the entire process with human cells within the next three months. However, it is likely to be at least a few years before researchers are ready to inject corrected cells back into a patient.
“Before we use this therapy in a human, we have to make sure every step of the process is working perfectly. We also want to increase the efficiency to have a large volume of cells ready to transplant,” Townes said. “I don’t want to over sell this, since there is still a lot of work to do. However, if we can make this therapy work as well in people as it does in mice, I have a lot of hope that it could be a real cure for sickle cell disease, and that the same approach could be used to develop treatment for patients with many other disorders.”