# In utero gene editing to cure a metabolic liver disease

> **NIH NIH R01** · CHILDREN'S HOSP OF PHILADELPHIA · 2021 · $737,588

## Abstract

PROJECT SUMMARY
Metabolic liver diseases are the second most common indication for a pediatric liver transplant. Hereditary
tyrosinemia type I (HT1) is a metabolic liver disease that results from FAH gene mutations causing a deficiency
in fumarylacetoacetate hydrolase (FAH), the last enzyme in the tyrosine catabolic pathway. HT1 can cause death
within the first months of life and has an increased risk of hepatocellular cancer (HCC) by mid-childhood. Liver
transplant is the only cure for HT1. Although lifelong treatment with nitisinone to inhibit hydroxyphenylpyruvate
dioxygenase (HPD) upstream of FAH has improved outcomes, some patients are resistant to nitisinone, and
HCC and liver failure have occurred despite the drug. Thus, there is a critical need to develop new strategies to
treat HT1 and other metabolic liver diseases. CRISPR-Cas9 gene editing offers an unprecedented opportunity
to treat genetic diseases. Base editing, a CRISPR editing approach that does not introduce double-strand DNA
breaks, is a potentially safer mechanism to silence a gene or correct a mutation than CRISPR-mediated
nonhomologous end-joining and homology-directed repair (HDR). In utero gene editing has the potential to
increase editing efficiency by taking advantage of fetal properties–small size, immunologic immaturity,
abundance of proliferative progenitor cells–and treat a disease prior to birth and the onset of irreversible
pathology. The overall objective of this proposal is to cure HT1 via in utero base editing and HDR. Our central
hypotheses are that intrinsic fetal properties will allow for efficient in vivo base editing and HDR to rescue the
lethal phenotype in HT1 mice, and that base editing, focused on treating HT1, will work efficiently in humanized
models. Our hypotheses are based on our preliminary data in which we 1) efficiently target the fetal liver via viral
and nonviral approaches, 2) silence the Hpd gene and rescue the HT1 mouse phenotype via prenatal base
editing, 3) identify guide RNAs targeting the human HPD gene for silencing via base editing, and 4) rescue the
HT1 phenotype via base editing to correct the Fah mutation in adult mice. Our rationale for these studies is that
they will establish the safety and feasibility of prenatal gene editing for HT1 as a model for metabolic liver
diseases. To attain our objective, we will pursue the following aims: 1) silence the Hpd gene via prenatal base
editing to cure the HT1 mouse phenotype and evaluate HPD base editing in humanized mouse models in vivo,
2) correct the FAH mutation via prenatal base editing in the HT1 mouse and in vitro in an engineered human cell
line, and 3) compare the efficiency and safety of prenatal and postnatal CRISPR-mediated and endonuclease-
free HDR and their ability to rescue the HT1 phenotype. Our research is innovative in the prenatal timing of novel
CRISPR and non-CRISPR gene editing approaches for HT1 and the study of HT1 base editing in humanized
models. The significant c...

## Key facts

- **NIH application ID:** 10093033
- **Project number:** 5R01DK123049-02
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** William H. Peranteau
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $737,588
- **Award type:** 5
- **Project period:** 2020-02-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10093033

## Citation

> US National Institutes of Health, RePORTER application 10093033, In utero gene editing to cure a metabolic liver disease (5R01DK123049-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10093033. Licensed CC0.

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