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Amit Nathwani, M.D. - "Haemophilia Gene Therapy"

Department of Haematology, University College London Cancer Institute, London, UK
When Sep 12, 2017
from 12:00 PM to 01:30 PM
Where Tigem Auditorium "Vesuvius"
Contact Name
Contact Phone 081-19230659
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Gene therapy for haemophilia A and B (factor VIII or factor IX deficiency respectively), the most common inherited bleeding disorders, offers the hope of a cure by facilitating continuous endogenous expression of factor VIII or factor IX following transfer of a functional gene to replace the haemophilic patient’s own defective gene. Haemophilia may be considered a ‘low hanging fruit’ for gene therapy because a small increment in blood factor levels (>2% of normal) significantly ameliorates the bleeding diathesis from severe to moderate phenotype, eliminating most spontaneous bleeds. The first trial to provide clear evidence of efficacy after gene transfer in patients with haemophilia B was recently reported by our group. A single peripheral vein infusion of adeno-associated virus (AAV) vector containing the factor IX (FIX) gene led to dose dependent increase in plasma FIX at therapeutic levels with no persistent ill effects. The only toxicity observed was transient subclinical transaminitis at the high dose level, which resolved following corticosteroid treatment. FIX expression has remained stable in most patients for >6years permitting these patients to discontinuation of FIX prophylaxis without increasing the risk of spontaneous haemorrhage. We have not observed any late toxicities. In the last 5 years six new AAV-haemophilia B gene therapy trials have begun with the most promising data emerging from studies using the gain-of-function Padua mutation in the FIX gene. Two studies have report a 8-10-fold enhancement of FIX catalytic activity to approximate averages of around 30% of normal FIX values. Further advance are likely to emerge through engineering of capsids to improve the efficiency of AAV gene transfer to the human liver using substantially lower vector doses, thus further improving the safety profile of this vector. This should positively impact on safety and cost of goods.
Progress has also been made with haemophilia A, a more challenging target for gene therapy. Using our codon optimised AAV-FVIII expression cassette a BioMarin sponsored study recently showed Factor VIII expression of between 12-150% in 7 severe haemophilia A patients recruited to the high dose cohort. Other gene therapy trials in haemophilia A have commenced and should be reporting soon.
Therefore, rapid progress is being made in the field of haemophilia gene therapy. Attention has to now shift on vector production to improve efficiency, quality whilst reducing costs. These and other aspects of haemophilia gene therapy will be discussed.

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