Academic Journal
Main Category: Blood / Hematology
Article Date: 10 Dec 2011 - 12:00 PST
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Patients with hemophilia B experienced considerable improvements and fewer injections with clotting factor to reduce bleeding after receiving just one treatment with gene therapy, researchers from St. Jude Children's Research Hospital, Memphis, USA, and University College London (UCL), England, reported in NEJM (New England Journal of Medicine).
The small Phase I study, involving just six patients, is still proof that gene therapy is a promising treatment for the disabling and potentially dangerous consequences of painful bleeding episodes experienced by patients with hemophilia B - an inherited blood disorder.
The authors say their study will be presented in San Diego, USA, on 11th December, 2011, at the 53rd annual meeting of the American Society of Hematology.
Four out of the six participants who received gene therapy no longer require further protein injections to prevent episodes of bleeding - none of those four have suffered bouts of spontaneous bleeding either. Some of them have gone on to take part in marathon running events and other activities which would have been extremely hard to do without the gene therapy.
All the patients were treated under the care of Prof. Edward Tuddenham at the Royal Free Hospital, London. Co-author Tuddenham is a pioneer in the field of blood coagulation.
First author Dr Amit Nathwani, said:
"This is a potentially life-changing treatment for patients with this disease and an important milestone for the field of gene therapy. It could have ramifications for the treatment of haemophilia A, other protein and liver disorders and chronic diseases such as cystic fibrosis."Hemophilia B (British spelling: haemophilia B) is a blood clotting disorder, as are all types of hemophilia. In this case it is caused by a mutation in the gene that makes Factor IX, an essential protein in the blood clotting process. It is the second most common form of hemophilia, after hemophilia A.
Hemophilia B is sometimes called Christmas disease, after Sephen Christmas, the first patient to be described with the condition. The disorder was also first published in the Christmas edition of the BMJ (British Medical Journal).
Nearly all patients with hemophilia B are male, because the mutated gene is carried on the X chromosome. The authors explain that it is a relatively rare condition, affecting approximately 1 in every 30,000 people.
Previous attempts at reducing the symptoms of hemophilia B by placing a correct copy of the gene have never been successful.
Prof. Tuddenham, Dr. Nathwani and team used AAV (adeno-associated virus) 8 to deliver the correct Factor IX gene, plus other genetic material into the liver of the patient. As the rate of natural infection with AAV8 is very low, it was picked up. AAV8 is part of a virus family that targets cells in the liver without causing illness in humans; neither does the virus integrate into human DNA.No immunosuppressant medications were administered to the participants before the gene therapy was given; an approach pioneered jointly by scientists from St. Jude and UCL.
A one-off infusion of the vector was administered into the vein in the arm of each patient. Two patients each received gradually rising doses of the vector. Afterwards, levels of Factor IX were elevated in all participants - from between 2% and 12% compared to less than 1% before the gene therapy began.
There was a correlation between dosages of the experimental vector and Factor IX levels - two volunteers, who were given the highest dosages, had the highest Factor IX levels. Their levels rose to up to 12%. The authors explained that any gain above 1% of normal levels can significantly improve patients' quality of life and reduce the number and severity of bleeding episodes.
Trial participant Sebastian Misztal (Source: UCLH/UCL NIHR Biomedical Research Centre)
Senior author, Dr Andrew Davidoff, said:
"The first patient has been followed for the longest time, and his levels have remained at 2% for more than 18 months. These results are highly encouraging and support continued research. More patients are scheduled to be enrolled in future trials scheduled to begin later this year."
The participant with the higher dosage had to undergo short-term steroid treatment, which was effective. His liver enzyme levels had risen slightly - a sign of mild liver damage - after receiving the vector infusion. His levels of Factor IX remain above what they were before gene therapy was applied, and his liver enzyme levels are back to normal. The other participant, who received the second highest dosage, also had slightly higher liver enzyme levels, but they did not rise beyond the normal range - he was also given a short course of steroids.
The authors say the rise in enzyme levels was most likely caused by an immune response. Immune responses were reported in previous gene therapy studies when a different vector was used.
Written by Christian Nordqvist
Copyright: Medical News Today
Not to be reproduced without permission of Medical News Today
Amit C. Nathwani, M.B., Ch.B., Ph.D., Edward G.D. Tuddenham, M.B., B.S., M.D., Savita Rangarajan, M.B., B.S., Cecilia Rosales, Ph.D., Jenny McIntosh, Ph.D., David C. Linch, M.B., B.Chir., Pratima Chowdary, M.B., B.S., Anne Riddell, B.Sc., Arnulfo Jaquilmac Pie, B.S.N., Chris Harrington, B.S.N., James O'Beirne, M.B., B.S., M.D., Keith Smith, M.Sc., John Pasi, M.D., Bertil Glader, M.D., Ph.D., Pradip Rustagi, M.D., Catherine Y.C. Ng, M.S., Mark A. Kay, M.D., Ph.D., Junfang Zhou, M.D., Yunyu Spence, Ph.D., Christopher L. Morton, B.S., James Allay, Ph.D., John Coleman, M.S., Susan Sleep, Ph.D., John M. Cunningham, M.D., Deokumar Srivastava, Ph.D., Etiena Basner-Tschakarjan, M.D., Federico Mingozzi, Ph.D., Katherine A. High, M.D., John T. Gray, Ph.D., Ulrike M. Reiss, M.D., Arthur W. Nienhuis, M.D., and Andrew M. Davidoff, M.D.
NEJM December 10, 2011 (10.1056/NEJMoa1108046)
Editorial - "Merry Christmas for Patients with Hemophilia B"
Katherine P. Ponder, M.D.
NEJM December 10th, 2011. DOI: 10.1056/NEJMe1111138
MLA
11 Dec. 2011.
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