# Gene Therapy for Alpha 1-Antitrypsin Deficiency

> **NIH NIH R61** · WEILL MEDICAL COLL OF CORNELL UNIV · 2024 · $422,895

## Abstract

Abstract. Alpha 1-antitrypsin (AAT) deficiency, an autosomal recessive disorder, manifests in lung as
early onset panacinar emphysema. AAT functions to inhibit neutrophil elastase (NE) and other neutrophil
serine proteases. AAT is produced predominantly in liver and diffuses into the lung from the circulation.
Low AAT levels in AAT deficiency are associated with an imbalance between AAT and neutrophil-released
proteases allowing slow destruction of the lung parenchyma. AAT deficiency is caused by mutation in the
SERPINA1 gene; M alleles are normal alleles, Z (E342K) homozygotes account for >95% cases. Z AAT
polymerizes in hepatocytes, limiting secretion, resulting in plasma levels 10-15% of normal. AAT inhibits
serine proteases through its active site centered at methionine (M) 351 and 358. The active site
methionines are modified by oxidants including cigarette smoke, air pollutants and endogenous oxidants
from activated inflammatory cells, reducing AAT function. AAT deficiency therapy is currently treated with
weekly infusions of AAT purified from human plasma; the infused AAT normalizes lung AAT levels,
protecting alveoli from destruction. While AAT augmentation therapy reduces the rate of lung destruction,
it is susceptible to oxidation, requiring excess “reserve” AAT to protect the lung. The focus of this proposal
is to translate to humans gene therapy for AAT deficiency that circumvents both weekly requirements for
protein therapy and the susceptibility of the therapeutic AAT to oxidation inactivation. We demonstrated
that replacing M351 with valine (V) and M358 with leucine (L) on a normal M1 alanine (A)213 background
provides anti-protease protection despite oxidant stress. One-time intravenous (IV) administration to mice
of AAV8hAAT(AVL), a serotype 8 adeno-associated virus vector coding for the oxidation resistant variant
hAAT(AVL) maintains high, dose-dependent anti-protease activity in serum and lung under oxidant stress
compared with normal AAT. A toxicology study over 6 months in C57Bl/6 mice demonstrated that IV
administration of AAV8hAAT(AVL) is safe. Based on the preclinical efficacy and safety data, we propose a
phase 1 safety/dose ranging study, with IV administration of AAV8hAAT(AVL) at each of 3 doses to n=5
AAT Z homozygotes at each dose. The highest dose [2x1013 genome copies (gc)/kg] is ~ ½ log lower than
the highest dose in the toxicity study. Aim 1, R61. Prepare and submit an Investigational New Drug
package and gain approval from the FDA and other regulatory groups to initiate a Phase 1 clinical trial.
Aim 2, R61. Optimize AAV8hAAT(AVL) production. Aim 3, R33. Manufacture clinical grade
AAV8hAAT(AVL) for the Phase 1 safety/dose-ranging clinical trial. Aim 4, R33. Carry out a Phase 1
safety/dose-ranging clinical trial to determine the highest tolerable dose and preliminary biologic efficacy of
AAV8hAAT(AVL) therapy for AAT deficiency.

## Key facts

- **NIH application ID:** 10859424
- **Project number:** 1R61HL169190-01A1
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** RONALD G CRYSTAL
- **Activity code:** R61 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $422,895
- **Award type:** 1
- **Project period:** 2024-05-15 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10859424

## Citation

> US National Institutes of Health, RePORTER application 10859424, Gene Therapy for Alpha 1-Antitrypsin Deficiency (1R61HL169190-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10859424. Licensed CC0.

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