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PO172-MON
Safety and efficacy of a novel AAV vector for treatment of hemophilia B
Anguela X1,2, Toso R2, Couto LB2, Chen Y2, Hui D2, DiPietro M2, Lee B1, Qu G2, Hauck B2, Corbau R1,2, Wright F2 and High KA2 1 The Children’s Hospital of Philadelphia; 2 Spark Therapeutics, Inc, Philadelphia, USA
Background: Liver-targeted delivery of AAV2/8 vectors encoding human factor IX (hFIX) has achieved recent clinical success for the treatment of hemophilia B (HB). However, significant challenges remain. While the clinical improvement in patients who achieved stable hFIX levels of around 5% of normal is indisputable, risk for excessive hemorrhage after trauma or surgery would be significantly reduced if stable levels were closer to 50%. Also, at least 50% of patients are not eligible for AAV8 treatment due to the presence of neutralizing antibodies (NAbs) that will block hepatocyte transduction.
Aims: The goal of this study was to evaluate the efficacy and safety of a novel bioengineered capsid (AAV-Spark100) containing the high specific activity hFIX-Padua variant.
Methods: FIX antigen and activity were monitored in non-human primates. NAb prevalence was measured in serum from HB patients.
Results: NAb prevalence against several AAV capsids was screened in ~60 patient sera. The % of samples with a NAb titer <1:1 was 58.9% for AAV-Spark100 vs. 45.3% for AAV8, indicating that ~10% more patients could potentially be treated with this novel capsid. Studies in non-human primates comparing the potency of AAV8 and AAVSpark100 showed comparable hepatic expression of hFIX, as well as similar biodistribution profiles. Using AAV-Spark100 expressing the hFIX-Padua transgene at a dose of 1 9 1012g kg1 , stable hFIX activity levels of up to ~35% of normal were achieved 3 months after treatment. There was no evidence of thrombosis in any animals, even those injected with a five fold higher dose and expressing as much as 350% normal hFIX activity, suggesting that this novel vector does not pose significant thrombogenicity risks. No vector-related changes in the hematology or clinical chemistry parameters were observed. Histopathological analysis revealed no gross or microscopic findings and no evidence of thrombosis.
Conclusion: Results from this study support the safety and efficacy of AAV-Spark100-hFIX-Padua hepatic gene transfer.
Disclosure of Interest: None declared.