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New sickle cell treatment now in beta-globin
August 2013
by Kelsey Kaustinen  |  Email the author


LOS ANGELESóA research team at the University of California, Los Angeles' (UCLA) Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, led by Dr. Donald Kohn, professor of pediatrics and of microbiology, immunology and molecular genetics, has developed a gene therapy approach for the treatment of sickle cell disease.  
Sickle cell disease is a condition in which the body produces blood cells with a crescent shape that makes it hard for the blood cells to travel easily through blood vessels, which deprives the body 's organs of oxygen and can lead to organ damage. Currently, treatment options for patients with sickle cell disease are generally limited to symptom management.  
This new approach is seeking to correct the issue at its source.  
The team began by taking the normal beta-globin gene and altered it to block the sickling activity, says Kohn.  
"We all have a gene that codes the beta-globin part of hemoglobin, and that's where the mutation is in sickle cell," Kohn explains. "So we took the normal human gene, and it's got a couple other changes to it that make it actually prevent the sickle hemoglobin proteins from sticking to each other. It's not something that exists in nature; it's sort of a 'designer gene' in a sense."  
This anti-sickling gene was then introduced into hematopoietic stem cellsóblood-producing stem cells found in the bone marrow. While transplants of donor hematopoietic stem cells currently exist as a treatment option for sickle cell disease, rejection risks are high. The benefit of this new approach is that it would use a patient's own stem cells, which would then be re-administered back to the patient like a regular bone marrow transplant. With the altered gene present, the stem cells are then coded to create normal, healthy red blood cells.  
"The transplanted cells, because they have this gene in them, the red cells that they make shouldn't sickle, and that would make those red cells have a normal lifespan, which is 120 days," says Kohn. "Whereas the remaining bone marrow that's making red cells that sickle, those have a short lifespan of maybe only 10 days, and so once it all reaches a steady state, most of the red cells should be the ones that don't sickle because they're lasting longer."  
In the lab, Kohn and his colleagues saw the altered stem cells producing non-sickled blood cells at a rate that could mean significant clinical improvement for patients. He says that at present, they are cautiously optimistic about the treatment's chances.  
"The results demonstrate that our technique of lentiviral transduction is capable of efficient transfer and consistent expression of an effective anti-sickling beta-globin gene in human sickle cell disease bone marrow progenitor cells, which improved the physiologic parameters of the resulting red blood cells," said Kohn.   Should this make it into patients, Kohn says that ideally, it would be a one-time treatment, just like a regular bone marrow transplant, and should last the lifetime of the patient.  
This approach has potential for other diseases as well, he adds, including severe combined immune deficiency syndrome, also known as "bubble baby syndrome." Other genetic blood cell diseases could benefit from such treatment as well. The team is also investigating the possibility of using this approach to modify stem cells to produce T cells that can fight cancer, and are exploring this in melanoma and leukemia.  
Kohn says he and his colleagues are now finishing the work required to apply for an investigational new drug permit from the U.S. Food and Drug Administration to start a Phase I clinical trial. They are aiming to submit the application by the end of this year, with hopes that the trial could start roughly a year from now. 

This study appeared online July 1 in the Journal of Clinical Investigation. Support came from the California Institute for Regenerative Medicine, UCLA's Broad Stem Cell Research Center and Jonsson Comprehensive Cancer Center and the Ruth L. Kirschstein National Research Service Award.  
Code: E081323



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