# Poly(amine-co-ester)s for Targeted Delivery In Vivo of Gene Editing Agents to Bone Marrow and Lung

> **NIH NIH UH3** · YALE UNIVERSITY · 2021 · $756,842

## Abstract

Project Summary
Hereditary disorders such as β-thalassemia and cystic fibrosis are attractive targets for genome engineering as
these maladies are curable upon correction of the disease-causing mutation. New technologies can catalyze
correction at the associated genomic site by homologous recombination (HR); for example, engineered
nucleases including CRISPR/Cas9 systems have shown promise and entered clinical trials. Alternative non-
nuclease-based triplex-forming peptide nucleic acids (PNAs) have also been successful in vivo. PNAs have no
intrinsic nuclease activity and enable activation of endogenous DNA repair activity when bound adjacent to the
target site and co-delivered with a donor DNA strand containing the corrected sequence. PNA-mediated gene
editing occurs via nucleotide excision repair (NER) and HR pathways and exhibits low off-target effects. While
these editing technologies have been successful thus far, important challenges remain before translation to the
clinic. The development of safe and effective delivery vehicles that are able to efficiently encapsulate gene
editing agents and target disease-relevant cells/tissues is necessary for the advancement of these
therapeutics. The goal of this research is to further the translation of genome engineering technologies
by developing biodegradable poly(amine-co-ester) (PACE) into polymeric vehicles that efficiently
encapsulate and deliver gene editing agents to target cells in the bone marrow and the lung upon
systemic intravenous (IV) administration. PACE is structurally diverse, allowing us to generate libraries of
vehicles and identify compositions for targeting bone marrow or lung. In preliminary work, we have observed
efficient encapsulation and delivery of gene editing agents using PACE. Further, specific PACE formulations
have exhibited favorable biodistribution to the bone marrow and lung. The project will proceed in two phases: a
development phase (UG3) and a demonstration phase (UH3). In the UG3 phase, a library of PACE polymers
with unique characteristics will be synthesized and tested for their ability to encapsulate PNA- and
CRISPR/Cas9-based editing reagents, deliver them to target cells, and promote efficient editing in vitro and in
vivo. Cell-type targeting and editing will be quantified using an innovative high-throughput single cell RNA
sequencing (scRNA-seq) screen. Candidate formulations targeting bone marrow and lung will be administered
to murine disease models of β-thalassemia and cystic fibrosis, respectively, to confirm their editing capabilities
and determine their ability to ameliorate disease symptoms. In the UH3 phase, candidate formulations and
gene editing agents will be scaled up to accommodate large animal studies, primarily in pigs, but also in non-
human primates in collaboration with other investigators in the SCGE program. These studies are designed to
confirm cell-type targeting, using quantitative measures of gene editing, and disease improvement, ...

## Key facts

- **NIH application ID:** 10274829
- **Project number:** 4UH3HL147352-04
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** PETER M GLAZER
- **Activity code:** UH3 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $756,842
- **Award type:** 4N
- **Project period:** 2018-09-07 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10274829

## Citation

> US National Institutes of Health, RePORTER application 10274829, Poly(amine-co-ester)s for Targeted Delivery In Vivo of Gene Editing Agents to Bone Marrow and Lung (4UH3HL147352-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10274829. Licensed CC0.

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