Thread by @DrSamelsonJones

@chowdarypm, @ProfMakris, and others report another successful #genetherapy for #hemophilia B clinical trial using the hyperactive FIX variant Padua.
tinyurl.com/346ty35v

🧵 on the clinical development of FIX Padua in gene therapy:

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This is now the 4th successful Phase1/2 #genetherapy study using #AAV vectors using FIX Padua. The initial demonstration of the benefit of FIX Padua in #genetherapy for #hemophilia B was in a study led by @LindseyAGeorge.

nejm.org/doi/full/10.10…

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This initial study was followed by
ashpublications.org/bloodadvances/…

thelancet.com/journals/lanha…

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However, Padua does not guarantee success! In an earlier trial, most recipients lost FIX expression because of a presumed capsid-immune response that was not responsive to immunosuppression, speculated due to CpG enrichment of the vector genome:

ashpublications.org/blood/article/…

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We demonstrated that the hyperactivity of FIX Padua is due to an enhanced interaction with cofactor FVIIIa

insight.jci.org/articles/view/…

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This mechanism results in predictable differences between one-stage and chromogenic FIX activity assays:

onlinelibrary.wiley.com/doi/full/10.11…

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That are likely due to differences in the rate and timing of FXIa and FVIIIa generation

ashpublications.org/bloodadvances/…

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