# Prenatal pulmonary cell gene editing to cure monogenic lung diseases

> **NIH NIH R01** · CHILDREN'S HOSP OF PHILADELPHIA · 2020 · $409,693

## Abstract

PROJECT SUMMARY
Congenital monogenic lung diseases, including cystic fibrosis, surfactant protein disorders, and alpha-1
antitrypsin deficiency (A1ATD), can cause perinatal respiratory failure and death or chronic lung disease. Despite
medical advances, therapy options are limited, often focused on treating disease complications, and culminating
in the need for a lung transplant for many patients. Thus, there is a critical need for novel therapies for monogenic
lung diseases. Many monogenic lung disease-causing mutations are well known, can be diagnosed before birth,
and, often, one mutation is responsible for the majority of cases. A G→A mutation (Glu342Lys, the PiZ allele) in
the SERPINA1 gene accounts for 90% of A1ATD mutations and results in severe disease, increasing the risk of
developing chronic obstructive pulmonary disease. Advances in CRISPR gene editing technology provide an
unprecedented opportunity to permanently correct disease-causing mutations in monogenic lung diseases after
a single treatment. Although encouraging, in vivo CRISPR gene editing studies targeting other organs in adult
mouse models of human diseases highlight limitations to the postnatal approach including low-levels of
homology directed repair (HDR) due to inaccessible and nonproliferative target cells and a mature immune
barrier. These obstacles are even more daunting in the postnatal lung, a barrier organ with immune and physical
barriers in which only 1% of epithelial progenitor cells, the target cell population for most lung diseases, are
cycling at homeostasis. In utero gene editing has the potential to overcome these barriers and treat perinatal
lethal diseases before the onset of irreversible pathology. The fetus is immunologically tolerant and progenitor
cells of multiple organs, including the lung, are highly proliferative and accessible during development. The
objective of this proposal is to establish the feasibility of prenatal lung gene editing and use prenatal gene editing
to treat a mouse A1ATD model as a model for monogenic lung diseases. Our central hypotheses are that
prenatal pulmonary cell gene editing is more efficient than postnatal editing and prenatal gene editing will not
have a detrimental effect on edited pulmonary progenitor cell fate. We hypothesize that prenatal HDR can provide
therapeutic levels of circulating alpha-1 antitrypsin protein and pulmonary cell gene correction in the A1ATD
mouse model. Our hypotheses are based on our published data demonstrating efficient liver and pulmonary
epithelial cell editing via prenatal CRISPR-nonhomologous end joining (NHEJ). To attain our objective, we will
pursue the following aims: 1) evaluate prenatal pulmonary cell gene editing in normal and neonatal injury states,
2) evaluate prenatal HDR targeting the lung and compare it to postnatal HDR, and 3) correct A1ATD by prenatal
HDR and compare it to postnatal HDR. Our research is innovative in the prenatal timing and targeting of the lung
for ther...

## Key facts

- **NIH application ID:** 9942201
- **Project number:** 1R01HL151352-01
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** William H. Peranteau
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $409,693
- **Award type:** 1
- **Project period:** 2020-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9942201

## Citation

> US National Institutes of Health, RePORTER application 9942201, Prenatal pulmonary cell gene editing to cure monogenic lung diseases (1R01HL151352-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9942201. Licensed CC0.

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