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Effect of Growth on AAV-mediated Expression of FIX-R338L in Juvenile Hemophilia B Dogs

T. Nichols1, S. Rakhe2, V. Arruda3, B. Samelson-Jones4, M. Caughey5, E. Merricks6, J. Murphy2, D. Pittman7

1Department of Medicine and Pathology and Lab Medicine, UNC, Chapel Hill, North Carolina, United States, 2Rare Disease Research, Pfizer Inc., Cambridge, Massachusetts, United States, 3Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States, 4The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States, 5UNC Biomedical Engineering, Chapel Hill, North Carolina, United States, 6UNC Department of Pathology and Lab Medicine (FOBRL), Chapel Hill, North Carolina, United States, 7Rare Disease Research, Pfizer Inc., Windham, New Hampshire, United States

Abstract Number: OC 21.4

Meeting: ISTH 2022 Congress

Theme: Hemophilia and Rare Bleeding Disorders » Hemophilia Gene Therapy

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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