Hemophilia gene therapy: a new vector – new successes
A long-term study led by Dr. Timothy Nichols from the University of North Carolina and Dr. Luigi Naldini from the San Rafael-Teleton Institute of Gene Therapy in Milan demonstrated the safety and effectiveness of a new method of hemophilia B gene therapy.
Hemophilia is a gender–linked hereditary disease that causes uncontrolled bleeding, often ending in early death of patients. With hemophilia A, the incidence of which is approximately 1 case per 5,000 male infants, the liver does not provide synthesis of sufficient amounts of blood clotting factor VIII. With hemophilia B, detected in 1 out of 35,000 male infants, there is no blood clotting factor IX in the body. Throughout life, patients with hemophilia have to make regular (up to several times a week) injections of appropriate blood clotting factors, but this does not provide complete protection from bleeding.
Gene therapy can radically change the situation, since it involves a single introduction of a therapeutic gene into the body, which will ensure stable synthesis of the missing protein for a long time.
Most often, adenoviral vectors are used for the development of gene therapy drugs. However, when selecting patients for clinical trials using such vectors, approximately 40% of potential participants revealed antibodies to adenovirus, which made them immune to treatment.
The authors propose to solve this problem with the help of an alternative vector developed by them, which is a modified lentivirus belonging to the retrovirus family. They removed from the genome of the virus the genes responsible for its replication, which did not deprive the virus of the ability to enter the body, but made it absolutely harmless to humans. At the same time, the vast majority of people do not have antibodies to lentivirus, which minimizes the likelihood of a decrease in the effectiveness of therapy due to the neutralization of viral vectors by the immune system.
(We recently wrote about the success of clinical trials on the first 10 volunteers of hemophilia B gene therapy using another vector – the adenoassociated virus).
Another advantage of the new lentiviral vector is its large size and, accordingly, the ability to transfer a large amount of genetic material. In this case, it is a fairly large gene encoding blood clotting factor IX. (This approach can also be used to treat hemophilia A, despite even larger changes in the gene encoding blood clotting factor VIII.)
Lentiviral vectors carrying the therapeutic gene of blood clotting factor IX were injected into three dogs with hemophilia B directly into the liver or intravenously. Before therapy, dogs developed an average of 5 spontaneous bleeds per year, requiring treatment in a clinic. More than three years after the therapy, the frequency of spontaneous bleeding in animals decreased to 0-1 times a year. At the same time, no undesirable side effects were registered in any of the animals.
To further confirm the safety of the approach, the researchers conducted experiments on three lines of mice with a high predisposition to the development of complications, such as the formation of malignant tumors, when foreign DNA is embedded in their genome. Despite the predisposition, no adverse side effects were recorded in any of the experiments in mice.
Despite the impressive results of animal experiments, the authors admit that there is still a lot of work to be done before conducting clinical trials. In particular, they plan to increase the effectiveness of therapy.
Before therapy, blood clotting factor IX was not registered at all in the body of experimental dogs, whereas after therapy, the production of this protein in the liver of animals was 1-3% of the normal index. This was enough to significantly reduce the risk of spontaneous bleeding. However, the researchers note that they would like to improve the developed approach in such a way that it provides an increase in the production of blood clotting factor IX to 5-10% of the normal level while maintaining safety for the patient.
Article by A. Cantore et al. Liver-directed lentiviral gene therapy in a dog model of hemophilia B is published in the journal Science Translational Medicine.
Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on the materials of the UNC School of Medicine:
New gene therapy for hemophilia shows potential as safe treatment.
13.03.2015