# Optimization of AAV vector to deliver FVa for hemophilia with inhibitors

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2022 · $625,580

## Abstract

ABSTRACT
Gene therapy with adeno-associated virus (AAV) vectors have been successfully applied in hemophilia
patients. However, the patients with inhibitors (antibodies against coagulation factors) are excluded from these
trials. AAV vectors have also been explored for delivery of a bypass product, FVIIa transgene, in preclinical
animal models. Although long-term improvement of hemostasis was achieved, the complete phenotypic
correction was not observed. During the coagulation cascade, FV (FVa) functions as a co-factor of FXa to
amplify thrombin generation. We pioneered a study in which FVa driven by a liver specific promoter was
constructed and packaged into AAV virions. After injection of AAV/FVa vectors into hemophilic mice,
completely phenotypic correction was achieved over 28 weeks without obvious complications. In this proposal,
we will explore an effective strategy using AAV vectors to deliver bypass products in the treatment of
hemophilia with inhibitors. First, we will optimize FVa constructs by utilization of different hepatocyte promoters
and modification of linker sequences between the FV heavy chain and light chain (Aim 1). Next, we will
explore whether the combination of AAV/FVa and AAV/FVIIa has a synergistic effect on the improvement of
hemostasis in hemophilic settings (Aim 2). Since the results obtained in mice experiments often do not
translate to large animal models, we propose to examine the long term phenotypic correction effect in
hemophilic dogs using AAV/FVa vector alone or in combination with AAV/FVIIa (Aim 3). Overall, the studies
proposed in the project will establish the basis for AAV vector-mediated bypass product gene transfer in future
clinical trials in hemophilia patients with inhibitors.
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## Key facts

- **NIH application ID:** 10372097
- **Project number:** 5R01HL144661-04
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Chengwen Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $625,580
- **Award type:** 5
- **Project period:** 2019-03-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10372097

## Citation

> US National Institutes of Health, RePORTER application 10372097, Optimization of AAV vector to deliver FVa for hemophilia with inhibitors (5R01HL144661-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10372097. Licensed CC0.

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