First successes
Gene therapy has shown efficacy against hemophilia B
Yulia Panchenko, PCR.news
Hemophilia B is a rare hereditary disease characterized by a lack of blood clotting factor IX (FIX). The gene encoding FIX is located on the X chromosome, so it is mainly men who suffer from hemophilia B. Currently, patients with this disease receive weekly injections of recombinant FIX to prevent bleeding, but such treatment is associated with significant side effects. The search for alternative therapy for hemophilia B continues
In a new study published in the New England Journal of Medicine (Chowdary et al. Phase 1-2 Trial of AAVS3 Gene Therapy in Patients with Hemophilia B), British and American scientists together with employees of the biotechnology company Freeline Therapeutics presented the results of Phase 1-2 clinical trial of gene therapy for the treatment of hemophilia B. The composition of the drug — FLT180a — includes an adeno-associated viral vector that carries FIX. The artificial capsid was designed in such a way as to transduce as many liver cells as possible. The FIX variant with the R338L mutation was also used, which increased its specific activity by about eight times compared to the wild-type factor.
Ten men over the age of 18 with a FIX level of no more than 2% of the norm took part in the clinical trial. Before the introduction of FLT180a, participants received therapy that suppressed their immunity for several weeks or months. After that, gene therapy was administered once in a dosage 3,84×1011, 6,40×1011, 8,32×1011 or 1.28×1012 vector genomes per kilogram of body weight. The condition of the participants was monitored for 26 weeks.
First of all, the safety of therapy was evaluated. None of the participants stopped therapy prematurely due to side effects. There were no deaths either. In 10% of cases, side effects were attributed to the effects of FLT180a, and in 24% of cases — to immunosuppressants. The first group of side effects included an increase in the level of alanine aminotransferase, muscle cramps and pain, myalgia, dyspepsia, thrombosis.
The authors also evaluated the effectiveness of therapy. In nine out of ten people, the FIX level increased depending on the dose, and the tendency to bleeding decreased. They no longer needed recombinant FIX therapy. After 26 weeks, five participants had a FIX level within the normal range (51-78%), three had a low level, but higher than initially (23-43%), and one participant who received the highest dose had a FIX level of 260%.
Thus, with the help of gene therapy, it is possible to achieve a normal FIX level in patients with hemophilia B. Nevertheless, in a clinical trial, cases have been identified where an immune response to therapy may manifest itself some time after gene therapy, often with the cancellation of immunosuppressants. The authors emphasize the need to monitor the level of alanine aminotransferase. Clinical trials are ongoing.
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