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Severe hemophilia B and AAV-mediated gene transfer: longer follow-up and expansion of the high dose cohort

Researchers have previously reported the preliminary safety and efficacy data of a novel gene transfer approach in six subjects with severe haemophilia B ( Nathwani et al,NEJM365:2357–65, 2011 ).
In brief, this entailed peripheral vein infusion of a serotype-8 pseudotyped self-complementary adeno-associated viral ( scAAV ) vector expressing a codon-optimised coagulation factor IX ( FIX ) transgene ( scAAV2/8-LP1-hFIXco ) at one of three vector doses: 2 • 1011 ( low ); 6 • 1011 ( intermediate ) and 2 • 1012 ( high ) vector genomes (vg)/kg.
A dose dependent increase in AAV-mediated expression of FIX at 1-6% of normal was observed in these individuals over an initial follow-up of between 6-14 months.

Extended follow-up of these individuals shows that FIX levels have remained stable in each of the initial participants over a period which is now greater than 2½ years following vector infusion.

In the subsequent phase of this study, researchers have recruited 4 additional severe haemophilia B subjects to the high dose cohort in order to better understand the safety and efficacy profile of scAAV2/8-LP1-hFIXco.
As before, scAAV2/8-LP1-hFIXco was administered without upfront immunosuppression at the time of vector administration.

The infusion of vector was well tolerated with no acute toxicity. Peak FIX activity in all four participants was greater than 5%, which is in keeping with what was observed in two subjects previously recruited at this dose level.
The mean steady state level for the entire high dose cohort ( n=6 ) is 5% of normal levels, which is sufficient to convert the bleeding phenotype fromsevere to mild.

Consistent with this, 5/6 subjects treated at the high dose level have not reported spontaneous bleeding episodes despite not being on regular FIX prophylaxis.
Transient asymptomatic increase in alanine transaminase over baseline values was observed in two of the four subjects recruited, occurring during weeks 7-9 post infusion.
The transaminitis resolved promptly and completely in both cases in response to a short course of oral Prednisolone while FIX expression was maintained.

These results have demonstrated that FIX expression is stably maintained at therapeutic levels for at least 2.5 years following AAV-mediated gene transfer to the liver.

Immune-mediated destruction of transduced hepatocytes appears to have occurred between 7-9 weeks after gene transfer in approximately two-thirds of the patients recruited at the high dose but was controlled with transient immunosuppressive treatment with oral Prednisolone.

These data are highly encouraging and suggest that AAV mediated gene transfer has the potential to change a severe bleeding phenotype of haemophilia B into a milder form for a prolonged period of time. ( Xagena )

Nathwani Ac et al,  Human Gene Therapy, 2013