# Optimized Gene Replacement for AAT deficiency and Modeling of Clinical Outcomes in small and large animal models

> **NIH NIH P01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2024 · $411,484

## Abstract

Project Summary (Project 1)
Alpha-1 antitrypsin deficiency (AATD) is a common single gene disorder caused by mutations in
the SERPINA1 gene, which normally encodes a very abundant serum antiprotease, whose
primary function is to protect the interstitial elastin matrix of the lung from degradation by
neutrophil elastase (NE). The E242K (PI*Z) mutant allele is very common among those of
European ancestry, and E342K homozygotes encode a protein with impaired secretion,
resulting in deficient serum levels, leading to unrestrained NE activity, degrading pulmonary
elastin. This process triggers lung inflammation and leads to loss of lung elastic recoil and
airways obstruction, creating the clinical picture of emphysema, which is the life-limiting effect of
AATD in most patients. Current AATD therapy consists of weekly IV infusion of AAT, but this
therapy has never been proven to benefit lung function in patients in prospective studies,
leading to questions about whether the previously identified serum target level (11 µM) is
sufficient, or whether gene therapy to restore such a level would be efficacious. Our laboratory
has previously developed rAAV gene therapy vectors and used them in clinical trials. Those
trials have failed to achieve the target, achieving levels just over 0.5 µM but being sustained
over 5 years in patients. We have also use CRISPR-based technology to produce the first
SERPINA1-knockout mice and have begun a collaboration with the University of Iowa group,
who have created both SERPINA1-knockout and SERPINA1-E342K ferret models. In the
current proposal, improved and optimized vectors will be tested in both mice and ferret models.
In the ferrets, they will be tested alongside sophisticated conditional transgenic reconstitution to
determine whether the optimal target for therapy is 11 µM vs. 25 µM. These studies will pave
the way for better rAAV-AAT vectors appropriate for future clinical product development.
In this project, we propose to study genetic emphysema due to alpha-1 antitrypsin deficiency
(AATD). AATD is both fairly common as a genetic disease and is a model of much more
common causes of chronic obstructive pulmonary disease (COPD). In the proposal, we will use
advanced gene editing tools to create genetically defined animal models of AATD (known as
transgenic animals), both in mice and in ferrets, which are a good model to study lung diseases.
In the course of the study, we will use both additional transgenic approaches and modified
recombinant viruses (rAAV) to genetically treat AATD in these models and examine how we
might design evaluate the effectiveness of future gene therapies for genetic emphysema.

## Key facts

- **NIH application ID:** 10914222
- **Project number:** 5P01HL158506-04
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Terence R. Flotte
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $411,484
- **Award type:** 5
- **Project period:** 2021-08-09 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10914222

## Citation

> US National Institutes of Health, RePORTER application 10914222, Optimized Gene Replacement for AAT deficiency and Modeling of Clinical Outcomes in small and large animal models (5P01HL158506-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10914222. Licensed CC0.

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