# Hepatic Gene Transfer for Treatment of Hemophilias A & B

> **NIH NIH R01** · STANFORD UNIVERSITY · 2021 · $697,224

## Abstract

The major objective of our work is to advance the scientific principles governing vector biology that will result in
improved gene transfer/genome editing approaches. All of the studies described in this proposal have the
potential to enhance gene therapeutics for the treatment of Hemophilias A and B. However, the work outlined
in the proposal is a platform technology that will advance gene therapeutics/genome editing. The ultimate goal
will be to provide a curative treatment after a single vector dose at the time of diagnosis. This will be important
not only for treating hemophilia but other inherited metabolic diseases. Specifically, we propose studies that
will further enhance nuclease-free AAV mediated homologous recombination (AAV-HR) strategies. We will
determine how factors that include host gene selection, composition of chimeric mRNA transcripts, tissue
regeneration, transcription, chromatin, R-loop, and direction and timing of DNA replication affect the efficiency
of AAV-HR and AAV-mediated HR transgene expression. We will also pursue preclinical strategies for
temporarily knocking down genes encoding proteins in the FANCM protein complex. Furthermore, we study
FDA approved drugs, which inhibit the ribonucleotide reductase complex and may enhance AAV-HR in the
liver. We will test a novel rAAV capsid variant we previously discovered, which has the capacity to package
larger genomes for its ability to package more robust classical AAV-human factor VIII expression cassettes
and allow for AAV-HR of the hFVIII coding sequence. The work outlined will not only address mechanistic
aspects related to AAV-HR but it will expand the utility of this approach and define potential limits to the current
technology.

## Key facts

- **NIH application ID:** 10187624
- **Project number:** 5R01HL064274-20
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Mark A Kay
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $697,224
- **Award type:** 5
- **Project period:** 2000-09-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10187624

## Citation

> US National Institutes of Health, RePORTER application 10187624, Hepatic Gene Transfer for Treatment of Hemophilias A & B (5R01HL064274-20). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10187624. Licensed CC0.

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