Gene therapy at UCL, St. Jude’s infuses hemophiliacs with hope

Study offers hope for men born with disabling blood disorder

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LONDON—Not having to worry about profuse bleeding andpainful bruising has infused new life into hemophiliac B patient SebastianMisztal, 31, following a single treatment with gene therapy developed byresearchers at St. Jude Children's Research Hospital in Memphis, Tenn., anddemonstrated to be safe in a clinical trial conducted by University College ofLondon (UCL).
The early success of this collaboration between twoprestigious institutions separated by an ocean offers first proof that genetherapy can reduce disabling, painful bleeding episodes in men born with theinherited blood disorder. Results of the Phase I study were revealed onlineDec. 10 in the New England Journal ofMedicine (NEJM).
"This is a potentially life-changing treatment for patientswith this disease and an important milestone for the field of gene therapy,"said first author Dr. Amit Nathwani of the UCL Cancer Institute's Royal FreeHospital. "It also could have ramifications for the treatment of hemophilia A,other protein and liver disorders and chronic diseases such as cysticfibrosis."
Hemophilia B "is a rare bleeding disorder affecting aroundone in 30,000 males who have problems with blood clotting," Nathwani states ina video shown on the UCL website. "Patients with hemophilia B lack the proteinin Factor IX so when we cut ourselves, the blood starts to coagulate to protectus from bleeding excessively."
Not so for those suffering from hemophilia B, once referredto as "bleeders." The key to opening the door to a solution was in finding areplacement for Factor IX. To solve that problem, researchers have taken out theproperties of Factor IX and placed a copy into a manmade virus to be infuseddirectly into the patient's liver, Nathwani says.
Previous efforts to ease hemophilia B symptoms byintroducing a correct copy of the gene have been unsuccessful.
In the current study, researchers used adeno-associatedvirus (AAV) 8 to deliver the Factor IX gene along with additional geneticmaterial into the patient's liver. AAV8 was picked because the incidence ofnatural infection with AAV8 is low. It belongs to a family of viruses thattarget liver cells, but do not cause disease in humans or integrate into humanDNA.
Participants in this study received no immune-suppressingdrugs prior to gene therapy. This approach was jointly pioneered by St. Judeand UCL, initially in the laboratory of study co-author Prof. Arthur Nienhuis,a member of the St. Jude Department of Hematology.
Following treatment, Factor IX levels rose in all sixpatients from less than 1 percent of normal levels prior to the gene therapy tobetween 2 and 12 percent, according to the co-authors.
Factor IX levels increased the most in the two studyvolunteers who received the highest dose of the experimental vector,researchers said. After treatment, levels of the protein ranged from 3 to 12percent in those men. Even modest increases that raise Factor IX production tomore than 1 percent of normal levels have the potential to dramatically affecta patient's quality of life and reduce bleeding episodes. 
Traditionally, hemophiliacs have been given a recombinantprotein, often several times a day, but this is an expensive and invasiveprocess, and not available to most of the world, says Dr. Andrew Davidoff,chair of the St. Jude Department of Surgery and the NEJM study's senior author.
"We are also interested in opening up this approach tochildren who may benefit from the treatment even more," Davidoff adds. "Thefirst patient has been followed for the longest time, and his levels haveremained at 2 percent for more than 18 months," Davidoff says. "These resultsare highly encouraging and support continued research. More patients arescheduled to be enrolled in future trials scheduled to begin later this year."
All six men, including Misztal, a company director/ownerfrom North Finchley in London, were treated at Royal Free Hospital in London.
"The vector was administered into six patients in total,which included Sebastian," he explains.
"Once injected with the vector, you become immune and can'tbe injected for a second time if it doesn't work," Misztal has stated. "But Iwas willing to take that risk. Nothing could be worse than what I have now. Itmight be too late for my ankles, as my joints were already very damaged by thehemophilia, but it could help others. It's been amazing. I've had no side effectsand I don't have to inject myself twice a week, which was not pleasant. MyFactor IX levels have increased and stayed constant. When I cut myself shaving,for example, the bleeding just stops—which wasn't happening before."
However, several steps must be taken before this genetherapy is available to the larger hemophilia B population—perhaps in five to10 years, says Nathwani.
Several of the other patient participants have alsoparticipated in marathons and other activities that would have been difficultprior to gene therapy.
One of the participants who received the highest dose of thevector underwent successful, short-term steroid treatment after his liverenzymes rose slightly after the vector infusion. The rise signaled mild liverdamage. The volunteer remained otherwise healthy, his Factor IX levels remainabove pre-infusion levels and his liver enzymes have returned to normal,according to the study.
The vector used in this study was produced at the GoodManufacturing Practices (GMP) facility on the St. Jude campus. The GMP operatesunder government-approved manufacturing guidelines and produces highlyspecialized medicines, vaccines and other products that pharmaceuticalcompanies are reluctant to pursue. The vector can also now be produced in asimilar facility at UCL.
The Hemophilia Society U.K.'s website states it "has beenfollowing research into gene therapy for hemophilia B patients with greatinterest."
"The Society is delighted to see world-class research in theU.K., which may ultimately provide therapies to improve the life of those withhemophilia showing such positive results at this stage," the website states."These are early days, and all medical and scientific developments need to gothrough extensive testing for efficacy and side effects. As such, we would notwish to raise false hopes at this stage. However, we hope that this researchwill eventually result in the removal of the need for regular injections andsignificantly reduce painful bleeds and debilitating joint damage for thoseliving with hemophilia."
Buoyed by the reaction of Misztal, Walker and others,Nathwani says he believes gene therapy "could revolutionize hemophilia B care. If we could make it work for hemophilia, we have every hope it can be used fordiabetes and cancer."

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