# Targeted expression of factor VIII in liver sinusoidal endothelial cells for gene therapy for hemophilia A

> **NIH NIH R01** · CHILDREN'S HOSP OF PHILADELPHIA · 2021 · $641,067

## Abstract

ABSTRACT
Hemophilia A (HA) is an X-linked bleeding disorder caused by a deficiency in coagulation factor VIII (FVIII).
Therapies aimed at even modest increases in clotting factor levels are associated with substantial improvement
of the severe disease phenotype. The current treatment for HA is protein replacement therapy, however, the
therapeutic landscape is rapidly changing for this disorder. Gene therapy approaches for adeno-associated viral
(AAV) vector delivery of FVIII are in clinical trials. Interestingly, these clinical studies target expression of FVIII
to hepatocytes using hepatocyte specific promoter elements which is based on the assumption that FVIII is
synthesized in hepatocytes. However, the primary site of FVIII synthesis was identified as the liver sinusoidal
endothelial cell (LSEC). While preclinical and clinical studies have demonstrated that hepatocytes can synthesize
functional FVIII, it has been challenging to produce high levels of FVIII after hepatocyte targeted expression. In
the ongoing AAV clinical studies for HA, there have been several unexpected observations. The first successful
AAV-hFVIII trial with the most patients (>13 subjects) and the longest follow-up (>3 years, ongoing) observed a
significant decrease in FVIII expression. All of the available clinical data from three trials to date shows a lack
of a vector dose response with significant variability among subjects. Importantly, these findings were not
observed in the AAV-FIX clinical studies suggesting that there is additional complexity to the delivery and
expression of FVIII. These unanticipated findings in the clinical studies may be related to the site of FVIII
synthesis. Thus, while significant hurdles have been overcome in gene therapy for HA, unexplored opportunities
for improved hemophilia patient outcomes remain. The goal of this proposal is to target FVIII expression to
LSECs using AAV vectors to study if there are biological differences in expressing FVIII in LSECs and
hepatocytes and to study the efficacy of AAV-FVIII delivery to LSECs. FVIII expression will be targeted to LSECs
using novel promoter elements (Specific Aim 1), novel AAV capsids that more specifically target AAV to these
cells will be identified (Specific Aim 2) and the biological differences between hepatocyte and LSEC derived FVIII
expression after AAV delivery will be investigated (Specific Aim 3). Together, these studies will provide the basis
for understanding the biology and efficacy of LSEC targeted AAV-FVIII expression to support the development
of this therapeutic approach for hemophilia A.

## Key facts

- **NIH application ID:** 10242722
- **Project number:** 5R01HL149833-02
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** DENISE E SABATINO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $641,067
- **Award type:** 5
- **Project period:** 2020-09-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10242722

## Citation

> US National Institutes of Health, RePORTER application 10242722, Targeted expression of factor VIII in liver sinusoidal endothelial cells for gene therapy for hemophilia A (5R01HL149833-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10242722. Licensed CC0.

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