Abstract Number: OC 21.4
Meeting: ISTH 2022 Congress
Background: The human liver doubles in mass 8-9 months from birth and again by 3-4 years. Liver growth and expanding blood volume may reduce FIX levels in pediatric recipients of hemophilia B (HB) gene therapy. HB dogs exhibit a similar phenotype and have proven to be highly predictive of the human experience with gene therapy. HB dogs with severe spontaneous bleeding can be monitored post-gene therapy to assess the effect of normal growth on FIX transgene levels and bleeding phenotype.
Aims: To determine the effect of growth on FIX levels in male juvenile HB dogs following treatment with an AAV-delivered, high-activity canine FIX-R338L.
Methods: Twelve HB dogs received an AAV encoding FIX-R338L variant under a liver specific promoter at age 3 or 6 months to model 2-6-year- or 6-12-year- old children, respectively. Six dogs per age group, were dosed at 5E+11 (2 dogs), 2.5E+12 (3 dogs) or 5E+12 (1 dog) vg/kg. Body weights, liver size (ultrasound), clinical chemistries and hemostatic activity were monitored by whole blood clotting (WBCT), thromboelastography (TEG) and activated partial thromboplastin time (aPTT).
Results: Dogs were followed for ≥12 months, during a period of liver growth (right lateral lobe: 35.7±5.4 to 93.5±10.6 mm, Figure 1) and blood volume expansion (estimated ~0.1 L to ~2 L). Treatment was well tolerated. To date, no spontaneous bleeds have occurred post-treatment. Increasing vector dose was associated with progressive shortening of clotting times (Figure 2). Stable, durable reductions of the aPTT, WBCT and TEG R values were observed in all dogs, indicative of FIX activity.
Conclusion(s): AAV-mediated gene therapy is associated with long-term correction of the laboratory and clinical phenotype of HB. This durable efficacy was observed in growing juvenile HB dogs treated at an early age (3 or 6 months) and was sustained for ≥ 1 year (ongoing observation) despite liver growth and blood volume expansion.
To cite this abstract in AMA style:Nichols T, Rakhe S, Arruda V, Samelson-Jones B, Caughey M, Merricks E, Murphy J, Pittman D. Effect of Growth on AAV-mediated Expression of FIX-R338L in Juvenile Hemophilia B Dogs [abstract]. https://abstracts.isth.org/abstract/effect-of-growth-on-aav-mediated-expression-of-fix-r338l-in-juvenile-hemophilia-b-dogs/. Accessed September 29, 2023.
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