# Approach for in vivo gene delivery into hematopoietic stem cells for hemophilia A therapy

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2021 · $592,575

## Abstract

ABSTRACT:
We will test a new approach for the production of therapeutic proteins secreted from blood cells after in vivo
gene delivery into hematopoietic stem cells (HSCs). This approach involves the mobilization of HSCs from the
bone marrow followed by a single intravenous injection of integrating helper-dependent HDAd5/35++
adenovirus vectors. HSCs transduced in the peripheral blood return to the bone marrow where they persist
long-term. Transgene integration is achieved either in a random pattern using a transposase or, in a site-
specific pattern, through homology-directed DNA repair mechanisms. For a secreted transgene product, we
will focus on human factor VIII expressed in erythrocytes after in vivo factor VIII gene transfer into HSCs. In
contrast to currently used rAAV-mediated liver-directed hemophilia gene therapy, our technically simple and
cost-efficient approach has the potential for a life-long cure with induction of tolerance to factor VIII. The
Specific Aims are 1. Increase the efficacy and safety of transposase-based HDAd5/35++ in vivo HSC
transduction through optimization of mobilization and vector injection regimens and through HSC in vivo
expansion or selection mechanisms. 2. Test new HDAd5/35++ vector systems for targeted integration,
including a vector that carries both a CRISPR-Cas9 to create site-specific DNA breaks and the homology
template for integration. 3. Test the best in vivo HSC transduction system in a mouse model for hemophilia A.
4. Perform a pilot safety and efficacy study in non-human primates, which are the most adequate model for
potential future studies in humans. The proposed 6-month study with repeated blood and bone marrow
sampling will allow us to predict potential long-term side effects on hematopoiesis and follow the expansion of
gene-edited HSCs over time.

## Key facts

- **NIH application ID:** 10162648
- **Project number:** 5R01HL141781-04
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** ANDRE Michael LIEBER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $592,575
- **Award type:** 5
- **Project period:** 2018-05-05 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10162648

## Citation

> US National Institutes of Health, RePORTER application 10162648, Approach for in vivo gene delivery into hematopoietic stem cells for hemophilia A therapy (5R01HL141781-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10162648. Licensed CC0.

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