# Human Genetic Disease Modeling and Physiology Core

> **NIH NIH P01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2021 · $192,625

## Abstract

Core B - Project Summary
To have successful therapies for Alpha-1 antitrypsin deficiency it is necessary to have animal
models that recapitulate the phenotypes see in human patients to test therapeutics, including
gene therapy and genome editing approaches, and develop clinically relevant therapeutic
benchmarks to ascertain the success of those therapies. To that aim this Core is working with
Project 1 (Flotte) to create an AAT-Null or PiZ ferret that conditionally expresses human AAT
(hAAT) as well as a murine model of the PiZ mutation on the background of the AAT knock-out
mouse created in our group.
The knock-out mouse recapitulates a lung phenotype with its complete lack of AAT production,
but does not completely model the state of the PiZ AAT patient who have some residual blood
levels of AAT that produce residual anti-elastase activity. In this Core we aim to create and
characterize an AAT-KO-PiZ mouse on the AAT-KO background and well as characterize an
existing AAT-KO/PiZ cross mouse. In addition to being a more relevant model to test gene
therapies, the AAT-KO-PiZ mouse will also serve as the model to further investigate genome
editing of the Z-AAT alleles in Project 2 (Xue). The current PiZ mouse contains multiple copies
of the PiZ gene, making it a non-ideal model for genome editing. Both mouse models will allow
us to elucidate further the role that the PiZ mutation plays without the presence of wild-type murine
AAT, something that has not been modeled in the mouse before. In Core B we will also produce
humanized liver NSG-PiZ mice to select for AAV serotypes that target human hepatocytes for
Project 3 (Wang).
In addition to the production of mouse and ferret models for use in Projects 1, 2, and 3 we will
also work with Projects 1 and 2 to characterize the pulmonary phenotype responses to gene
therapy and genome editing. The core will offer novel expertise in rodent pulmonary function
testing, bronchoalveolar lavage testing and facilitation of lung computed tomography in
collaboration with Dr. Bankier and Tufts Cummings School of Veterinary Medicine.

## Key facts

- **NIH application ID:** 10270091
- **Project number:** 1P01HL158506-01
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Alisha Marie Gruntman
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $192,625
- **Award type:** 1
- **Project period:** 2021-08-09 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10270091

## Citation

> US National Institutes of Health, RePORTER application 10270091, Human Genetic Disease Modeling and Physiology Core (1P01HL158506-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10270091. Licensed CC0.

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