# Models and Gene Therapies for AAT Deficiency

> **NIH NIH P01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2022 · $2,676,698

## Abstract

Project Summary (OVERALL)
Alpha-1 antitrypsin deficiency (AATD) is caused by mutations in the SERPINA1 gene. The
E342K (PI*Z) mutant allele is very common among those of European ancestry, and E342K
homozygotes encode a protein with impaired secretion, resulting in deficient AAT serum levels.
Since AAT normally protects elastin in the lung from degradation, loss of effective AAT triggers
lung inflammation, airways obstruction and emphysema, which is the primary life-limiting
manifestation of AATD. The projects within this proposal seek to pursue numerous parallel
strategies to develop a gene therapy for AATD. Most of these strategies revolve around the use
of recombinant adeno-associated virus (rAAV)-based vectors, a platform technology that has
been very successful for other genetic diseases. In Project 1, optimized rAAV vectors will be
studied in genetically defined animal models (including mice and ferrets) in comparison with
transgenic reconstitution studies using a regulated conditional transgenic system to compare
two relevant potential target replacement levels (11µM and 25µM) and clinically relevant
endpoints will be studied. In Project 2, novel CRISPR variants will be used for gene editing,
base editing and prime editing strategies to treat AATD. In Project 3, we will screen naturally
occurring AAV capsid libraries obtained from remote populations in Western China to identify
capsids with enhanced efficacy and safety for AATD gene therapy. Finally, in project 4, we will
use novel Treg and CAR-Treg strategies to selectively modulate anti-vector immune responses.
There will also be two cores. Core A will provide each project with important Vector
Immunology assays, which can identify limitations due to host immune responses to AAV
capsids, the AAT transgene or to Cas9-derived proteins. Core B will provide animal models and
physiologic measurements in the animal models for testing of optimized rAAV vectors, gene
editing tools and immune modulation approaches. Program investigators have a track record of
interactions and collaborations that we anticipate will continue in future years.

## Key facts

- **NIH application ID:** 10463802
- **Project number:** 5P01HL158506-02
- **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:** 2022
- **Award amount:** $2,676,698
- **Award type:** 5
- **Project period:** 2021-08-09 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10463802

## Citation

> US National Institutes of Health, RePORTER application 10463802, Models and Gene Therapies for AAT Deficiency (5P01HL158506-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10463802. Licensed CC0.

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