# Postnatal and Prenatal Therapeutic Base Editing for Metabolic Diseases

> **NIH NIH U19** · CHILDREN'S HOSP OF PHILADELPHIA · 2024 · $5,051,652

## Abstract

PROJECT SUMMARY
The potential for the development of novel therapeutic modalities has energized the genome editing field since
it first emerged in the 1990s and especially since the demonstration of programmable genome editing with
CRISPR-Cas9 by multiple groups in 2012. There has been substantial progress with ex vivo therapeutic
applications of genome editing in patients in the past few years, most notably with CAR-T immunotherapies for
cancer and with durable treatment of hemoglobinopathies. Progress with in vivo therapeutic applications, i.e.,
somatic cell genome editing, has been slower due to the technical challenges inherent in the delivery of genome-
editing tools into the body. As of the time of this writing, there are few published examples of successful genome
editing performed in vivo in primates (including humans), with almost all examples involving somatic genome
editing in the liver: TTR with Cas9 nuclease delivered by lipid nanoparticles (LNPs), PCSK9 and ANGPTL3
with adenine base editors delivered by LNPs, and PCSK9 with meganucleases delivered by adeno-associated
virus (AAV) vectors. The prospects for genome-editing therapies extend to before birth, with in utero genome
editing having the potential to treat genetic diseases that result in significant morbidity and mortality before or
shortly after birth. Although restricted to small animal models so far, in utero genome editing has proven effective
in the liver, lungs, heart, and other organs.
Our Overall Program seeks to build on these early successes, pursuing goals that that would be of major impact
in advancing the field of therapeutic genome editing. Our three Research Projects seek to develop base-editing
therapies targeting the liver in order to treat three rare metabolic genetic diseases: phenylketonuria (PKU),
hereditary tyrosinemia type 1 (HT1), and mucopolysaccharidosis type 1 (MPSI). Lead Project 1 will focus on
LNP-based postnatal treatment of PKU, with the aim to file an IND application by the end of the five-year
funding period and begin a phase 1/2 clinical trial soon afterwards. Project 2 will focus on LNP-based postnatal
treatment of HT1, with the aim to file an IND application and begin a clinical trial, and prenatal treatment of
HT1, with the aim of performing preclinical studies during the five-year funding period to enable an eventual IND
application if the postnatal clinical trial proves successful. Project 3 will focus on AAV-based postnatal and
prenatal treatment of MPSI, with similar aims as Project 2. Unique, specialized Resource Cores focused on
off-target editing and in utero treatment of small and large animals will be indispensable in achieving these aims.

## Key facts

- **NIH application ID:** 10896255
- **Project number:** 5U19NS132301-02
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Kiran Musunuru
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $5,051,652
- **Award type:** 5
- **Project period:** 2023-08-01 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10896255

## Citation

> US National Institutes of Health, RePORTER application 10896255, Postnatal and Prenatal Therapeutic Base Editing for Metabolic Diseases (5U19NS132301-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10896255. Licensed CC0.

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