Improvements in Haemophilia Therapies Addressed at Vienna Congress

Vienna , June 8, 2007 - There are two forms of haemophilia. Haemophilia A is the most common and involves a defect in Factor 8, one of the major clotting factors. Haemophilia B is a defect of one of the other major clotting factors, Factor 9. But at the end of day, sufferers face the same problems, says Professor Thierry VandenDriessche from the Centre for Transgene Technology and Gene Therapy at the University of Leuven in Flanders, Belgium. They face bleeding from injury, as is well known, but also spontaneous bleeds. In the joints, a spontaneous bleed can cripple, in the brain, it can be lethal.

One of the hallmarks of haemophilia is that therapies don’t need to normalise blood clotting factors to bring a marked improvement in a patient’s condition. People with severe haemophilia may have less than 1% of normal clotting factor levels. But even an improvement of up to 2 to 5% makes a major difference, and can change a patient’s condition from severe to mild haemophilia.

New gene therapies target liver and muscles

The organ most commonly targeted at the moment in gene therapies for haemophilia is the liver. Clotting factors in healthy people are produced in the liver so this is an obvious and most important target. But the liver is not the only organ of interest in current developments in the field. Clinical trials have been conducted in which the muscles have been targeted. One of the advantages in human gene therapy is that clotting factors are secreted into the blood stream, so that it doesn’t matter which organ is the source. Professor VandenDriessche in his presentation at the 12th Congress of the European Hematology Association in Vienna (June 6 to 10, 2007) on both muscle and liver sources, of which the liver at the moment is still the most successful for expression of genetically engineered improvements in production of clotting factors.

A key issue in gene therapy is vectors, the cellular vehicles which deliver the “new” genetic information to a patient’s organs. Identifying the most efficient and safest vectors, with least possible side effects, is a key area of research in gene therapy for haemophilia at the moment. The field needs to move beyond small animal studies to pre-clinical studies in large animals. It is already clearly established that some vectors are more efficient than others. Historically, the safest and best vectors are Adeno Associated Virus vectors (AAV). With most vectors available now, gene therapy can improve clotting factors from less than 1 to over 10% for weeks at a time, but levels then decline again. “A lot of work is being done, and has still to be done, on why expression decreases and what to do about it”, says Professor VandenDriessche. Two trials of AAV, one targeting muscle tissue, the other the liver, have produced encouraging results. Gene expression in the muscle lasted longer, but was not high enough. The opposite results were obtained with the liver, in which expression was higher, but briefer. Also in those patients who have received gene therapy targeting muscles, there is evidence of Factor 9 production in skeletal muscle several years later, though production is not achieved at high enough levels to detect it in blood.

Significant improvements within reach

A crucial issue for researchers at the moment is to identify optimal vectors so that doses can be lowered. Side effects from vectors under study vary significantly, and no generalisations can be made in this respect.With AAV, there are no side effects with low and intermediate doses. High doses trigger short term liver inflammation, which illustrates the importance of developing an approach allowing lower doses.Professor VandenDriessche is among haematology experts worldwide working in this field, and says significant improvements are within reach: “Those vectors being tested in labs at the moment are already better than those in clinical trials.”

Inhibitor reactions are also a key issue. “Inhibitors” occur when the immune systems of some people with haemophilia develop antibodies after treatment with Factor 8 concentrate. Interpreting the concentrate as a foreign substance, the antibodies destroy it. Inhibitor reactions in gene therapy are unclear as yet, but data are encouraging. Small animal studies suggest a diminished risk of inhibitor development in gene therapy. Professor VandenDriessche says too little is known to make any definitive statements, “but data point in the right direction.“

Gene therapy may offer long term correction of clotting factor deficiencies

Another interesting development in gene therapy involves the “ex viro” approach. This entails removing patient cells, genetically engineering them and reintroducing them to the patient’s body.One interesting avenue is the possibility of expressing clotting factors in blood platelets, which are vital to ensuring a stable plug to stop bleeding at the moment of injury. This is conceptually a very attractive approach, since it delivers a correction at the right place at the right time, where you have a bleed.

“In general, there is strong evidence that gene therapy for haemophilia sufferers may eventually offer long term correction of blood clotting factor deficiencies”, Professor VandenDriessche says.

Also at the Vienna EHA Congress, Professor Claude Négrier from the EdouardHerriotUniversityHospital in Lyon in France, presented new developments in products for classic haemophilia treatments. Professor Négrier described the haemophilia comprehensive care centre concept used in his hospital, detailing costs and benefits to patients.

In general new products have higher specific coagulant activity and extended half life. None of these products are used in therapies yet, though one is now at the clinical trial stage. They can be expected to be in use within 5 to 6 years.

One of the most promising aspects is the reduction in frequency of treatment. This is particularly relevant for treatment of children who with current medication must undergo intravenous treatment as often as three times a week. With new products offering improved blood coagulants, intravenous therapy can be reduced to once a week, which represents a dramatic improvement in quality of life.

Professor Négrier says: “The new products under consideration and gene therapy are not mutually exclusive and represent complementary approaches to improving the outlook for haemophilia sufferers.”

Contact:

B&K Medien- und Kommunikationsberatung GmbH
Dr. Birgit Kofler; Daniela Pedross, MA.
Porzellangasse 35/Top 3, A-1090 Vienna
Phone: 0043-(0)676-6368930; Fax: 0043-01-319-43-78-20
E-Mail: kofler@bkkommunikation.at; pedross@bkkommunikation.at

About EHA

The European Hematology Association (EHA) aims to promote excellence in clinical practice, research and education in European hematology.

Today, EHA – with over 2600 active members from 95 countries – is a consolidated organization that pursues a large and growing number of projects and programs. An Executive Board and Councilors elected by the membership form the governmental body responsible for the strategy and organization of the association.

About the EHA Annual Congress

The EHA annual congress is organized every June in a major European city. Over the years the congress has become the meeting place for hematologists in all fields of the speciality. The congress program has sessions on clinical and laboratory hematology and covers all the major hematological subspecialties, including hemato-oncology, red cell disorders, hemostasis, thrombosis, pediatric hematology and transfusion medicine.