A Significant Advancement in Gene Therapy for Haemophilia
A study at the St. Jude Children’s Research Hospital led by Amit C. Nathwani has determined that the gene transfer of Factor IX, a protein in the coagulation system that assists in blood clotting, is an important factor for the restoration of patients that suffer from server haemophilia B.
Haemophilia B is disorder that is a result of a deficiency of a coagulation protein, Factor IX or FIX. The severe cases of Haemophilia B are considered to have less than 1% of the FIX level of a normal person. The current method of treatment is to have the patient to be regularly injected with a FIX protein concentrate, two or three times a week, which is a temporary and a costly option. This study is to determine if the infusion of a self-complementary Adenovirus-Associated Virus (scAAV) vector which acts as a carrier for the FIX gene into the body, results in an increase of the patients FIX levels over a long period of time, and only with assistance from the prophylactic FIX injections if any participants FIX level will need intervention.
Six participants who had a severe case of very low FIX levels, and had to have no neutralising antibodies to AAV8; a vector that would enable gene transfer through the peripheral vein, and subsequently into the liver (Nathwani et al. 2011). The 6 participants would be categorised into 1 of 3 subsequent groups, with each group being administered into these dose levels: “low (2x10^11 vector genomes [vg] per kilogram of body weight), intermediate ( 6x10^11 vg per kilogram), and high (2x10^12 vg per kilogram)” (Nathwani et al. 2011).
Within the results (Figure 1), all of the participants had a long-term increase by at least 1.5%, though the participants that were administered high dosage levels of the vector had elevated levels of alaline and aspartate aminotransferase, having an immune response to the FIX levels around approximately week 10 after the vector infusion, which was counteracted back to normal levels with a glucocorticoid, 60mg of prednisolone (Nathwani et al. 2011). There were also no immune responses after the vector infusion in any participant at any time, however some participants such as participants B, C and E needed prophylactic FIX injections over the course of the investigation in certain situations such as prevention of bleeding from a traumatic event during a field trip or intervention to stop their FIX levels from decreasing any further (Nathwani et al. 2011).
From the study, Nathwani (2011) concluded that the infusion of a self-complementary Adenovirus-Associated Virus vector “consistently leads to long-term expression of the FIX transgene at therapeutic levels, without acute or long-lasting toxicity in patients with severe haemophilia B” (Nathwani et al. 2011). He also deduced that “Immune-mediated, AAV-capsid–induced elevations in aminotransferase levels remain a concern, but our data suggest that this process may be controlled by a short course of glucocorticoids, without loss of transgene expression” (Nathwani et al. 2011). Hopefully this breakthrough in research of Factor IX will eventually progress into permanent solution for Haemophilia.