# SCGE Disease Models Studies Supplement: Evaluation of prime editing for the amelioration of alpha-1-antitrypsin deficiency in murine and porcine models.

> **NIH NIH U24** · RECOMBINETICS, INC. · 2022 · $165,970

## Abstract

PARTICIPATING AWARDS, INVESTIGATORS & INSTITUTIONS
4UH3TR002668-04, “Enhancing CRISPR Gene Editing in Somatic Tissues by Chemical
Modification of Guides and Donors”, Drs. Erik Sontheimer and Scot Wolfe, University of
Massachusetts Chan Medical School
1U24OD026641-01, “Development of Swine Reporter Models for Testing Somatic Cell Genome
Editing Tools.”, Drs. Daniel Carlson and Jarryd Campbell, Recombinetics
ABSTRACT
Alpha-1 antitrypsin deficiency (A1AT) is a hereditary disorder caused by point mutations in
SERPINA1 (SERine Proteinase INhibitor A1) that is characterized by low serum and low lung
levels of AAT. The most common mutation is the “Z” (Glu342Lys) allele that reduces AAT in
circulation due to retention in the liver leading to overactive proteases in the lung, and
accumulation of the mutant misfolded AAT protein in hepatocytes. This leads to tissue destruction
in the lungs (loss-of-function), and liver disease (gain-of-toxic-function) in many A1AT patients.
More than 95% of people with severe A1AT are homozygous for the Z allele (PI*ZZ).
The ideal therapeutic would repair the PiZ allele. Unfortunately, A1AT gene therapy to treat even
one target pathology (lung or liver) has not yet been effectively translated to patients despite
promising data in early mouse models of A1AT. Our team brings together expertise in A1AT gene
therapy, preclinical animal models, RNA delivery, and prime editing technology. We propose to
develop optimized prime editing reagents to repair the PiZ allele. With these reagents, we will
perform dosage escalation studies in two unique mouse models of A1AT to measure gene repair
outcomes and the subsequent effect on lung and liver phenotypes. The optimal dose from mice
will be evaluated in our novel, humanized swine model of the PiZ allele with the primary goal of
evaluating safety and target engagement. We believe this stepwise paradigm for therapeutic
evaluation in two animal models will improve the likelihood of a successful outcome in subsequent
clinical studies.

## Key facts

- **NIH application ID:** 10625217
- **Project number:** 3U24OD026641-05S1
- **Recipient organization:** RECOMBINETICS, INC.
- **Principal Investigator:** Daniel Fred Carlson
- **Activity code:** U24 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $165,970
- **Award type:** 3
- **Project period:** 2018-09-20 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10625217

## Citation

> US National Institutes of Health, RePORTER application 10625217, SCGE Disease Models Studies Supplement: Evaluation of prime editing for the amelioration of alpha-1-antitrypsin deficiency in murine and porcine models. (3U24OD026641-05S1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10625217. Licensed CC0.

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