Changing a Gene in People Who Have Beta Thalassemia or Other Blood Disorders Works Wonders.

Gene therapy helps patients avoid blood transfusion

Even though it rarely affected her dance lessons, she also remembers being sick -- very sick. Sihanath, now 22, was diagnosed as a young child with the genetic blood disorder beta thalassemia. She was treated with occasional blood transfusions, which became monthly when she turned 14.

From article, (Beta thalassemia is an inherited blood disorder caused when the body doesn't make enough of a protein called hemoglobin, an important part of your red blood cells. It's found around the world, occurring most frequently in people from Mediterranean countries, North Africa, the Middle East, India, Central Asia and Southeast Asia. The total incidence of symptomatic cases each year is estimated to be about 1 in 100,000 people throughout the world.

In general, thalassemia can be well-managed with blood transfusions and chelation therapy which removes excess iron from the body with drugs, according to the US Centers for Disease Control and Prevention. Most people with severe anemia from thalassemia require red blood cell transfusions every two to three weeks.

The new study suggests a way to cut the need for those transfusions. It involved two trials with 22 patients total, 12 to 35 years old, with transfusion-dependent beta thalassemia. Transfusion dependence was defined in the study as having to receive at least eight transfusions per year, or at least 100 milliliters per kilogram of body weight of red blood cells per year, in the two years prior to enrolling in the study.

The two trials were to evaluate the safety and efficacy of a gene therapy for beta thalassemiausing LentiGlobin, an investigational therapy by Bluebird Bio. It works by inserting a functional human beta hemoglobin gene into a patient's own stem cells outside the body and then transplanting those modified cells back into the patient's blood stream.

One of the trials in the study, called HGB-204, included 18 patients and was conducted at six sites around the world: four in the United States, one in Australia and one in Thailand. The other trial, HGB-205, included four patients and was conducted at Necker Children's Hospital in Paris.

In all of the patients, their own stem cells were harvested in a process involving the use of the drugs filgrastim and plerixafor, which move stem cells from the bone marrow to the bloodstream. Once the stem cells were collected, they were sent to a lab where they were transduced with LentiGlobin, which inserted that healthy beta-globin gene.

To prepare their bodies for the gene therapy, patients then underwent four days of the chemotherapy drug busulfan intravenously. Next, their modified stem cells were transplanted back into their bodies. After transplantation, they were monitored and followed up with during a period ranging from 15 to 42 months.

The researchers found that, "of those 22 patients, 15 of those patients became transfusion-independent, which meant that they were not transfused for a minimum of a one-year period," Thompson said. "For some, now it's been even much longer than a one-year period."

The researchers also found no serious adverse side effects related to the gene therapy and no significant unexpected safety issues.
"The side effects that were seen in these two clinical trials are consistent with what we expect from a transplant of any kind that uses chemotherapy," Thompson said.

There were five mild adverse effects in the HGB-204 trial and nine serious adverse events, including two episodes of veno-occlusive liver disease, attributed to the chemotherapy. In the HGB-205 trial, all four patients had adverse events related to the chemotherapy, such as mouth sores.

"There were no novel side effects identified that related either to the LentiGlobin vector or the gene therapy procedure itself," Thompson said. "We clearly want to watch for a much more extended period of time to be sure that there are no additional safety concerns."

In separate studies, some of the same researchers had tested the feasibility of transferring a healthy beta-globin gene into the cells of a beta thalassemia patient. In 2010, they first reported the successful use of the gene therapy for beta thalassemia in a patient.

Now, the findings in the new study appear to expand on that idea.

LentiGlobin is also being tested in patients with sickle cell disease, another group of inherited red blood cell disorders, which suggests that the therapy might have potential to be widely used for various diseases.

Dr. Douglas Higgs, professor of hematology and director of the MRC Haematology Unit at the University of Oxford in England, called the new study "important."

"Even though this is the best we can achieve at the moment, not all patients become free of transfusions and we still do not know the long-term effects of manipulating the genome of stem cells in this way," Higgs said in a statement.

"A major question hanging over this approach, which is hugely expensive, is whether this procedure, which involves killing off abnormal stem cells to replace them with modified stem cells, will ever become clinically possible in developing countries where the majority of these disorders of hemoglobin occur," he said.)

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