New sickle cell treatment now in beta-globin

UCLA researchers set to advance gene therapy into clinical trials

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LOS ANGELES—A research team at the University of California,Los Angeles' (UCLA) Eli and Edythe Broad Center of Regenerative Medicine andStem Cell Research, led by Dr. Donald Kohn, professor of pediatrics and ofmicrobiology, immunology and molecular genetics, has developed a gene therapyapproach for the treatment of sickle cell disease.
Sickle cell disease is a condition in which the bodyproduces blood cells with a crescent shape that makes it hard for the bloodcells to travel easily through blood vessels, which deprives the body's organsof oxygen and can lead to organ damage. Currently, treatment options forpatients with sickle cell disease are generally limited to symptom management.
This new approach is seeking to correct the issue at itssource.
The team began by taking the normal beta-globin gene andaltered it to block the sickling activity, says Kohn.
"We all have a gene that codes the beta-globin part ofhemoglobin, 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 itthat make it actually prevent the sickle hemoglobin proteins from sticking toeach other. It's not something that exists in nature; it's sort of a 'designergene' in a sense."
This anti-sickling gene was then introduced intohematopoietic stem cells—blood-producing stem cells found in the bone marrow.While transplants of donor hematopoietic stem cells currently exist as atreatment option for sickle cell disease, rejection risks are high. The benefitof this new approach is that it would use a patient's own stem cells, whichwould then be re-administered back to the patient like a regular bone marrowtransplant. With the altered gene present, the stem cells are then coded tocreate normal, healthy red blood cells.
"The transplanted cells, because they have this gene inthem, the red cells that they make shouldn't sickle, and that would make thosered cells have a normal lifespan, which is 120 days," says Kohn. "Whereas theremaining bone marrow that's making red cells that sickle, those have a shortlifespan of maybe only 10 days, and so once it all reaches a steady state, mostof the red cells should be the ones that don't sickle because they're lastinglonger."
In the lab, Kohn and his colleagues saw the altered stemcells producing non-sickled blood cells at a rate that could mean significantclinical improvement for patients. He says that at present, they are cautiouslyoptimistic about the treatment's chances.
"The results demonstrate that our technique of lentiviraltransduction is capable of efficient transfer and consistent expression of aneffective anti-sickling beta-globin gene in human sickle cell disease bonemarrow progenitor cells, which improved the physiologic parameters of theresulting 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, headds, including severe combined immune deficiency syndrome, also known as"bubble baby syndrome." Other genetic blood cell diseases could benefit fromsuch treatment as well. The team is also investigating the possibility of usingthis 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 workrequired to apply for an investigational new drug permit from the U.S. Food andDrug Administration to start a Phase I clinical trial. They are aiming tosubmit the application by the end of this year, with hopes that the trial couldstart 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'sBroad Stem Cell Research Center and Jonsson Comprehensive Cancer Center and theRuth L. Kirschstein National Research Service Award.

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