Treating alpha-1 antitrypsin deficiency by targeting cellular protein-folding pathways
Official title: Managing Alpha-1-Antitrypsin Deficiency (AATD) through Proteostasis Signaling Pathways
Funded at Scripps Research Institute, the · NIH-11285254 · Data updated 2026-11-12
This project uses small molecules to fix how cells fold alpha-1 antitrypsin so people with different genetic forms of alpha-1 antitrypsin deficiency may keep healthier livers and lungs.
Quick facts
| Grant type | R01 grant |
|---|---|
| Study type | NIH-funded research |
| Funding institution | Scripps Research Institute, the NIH-funded |
| Lab location | 1 site (La Jolla, United States) |
| Project start | March 15, 2024 |
| Project end | February 29, 2028 |
| Funding year | 2026 |
| Award (this year) | $855,694 |
| NIH project number | 5R01HL169631-03 |
| Project ID | NIH-11285254 on NIH RePORTER |
Who could benefit from this research
✓Could help
People diagnosed with alpha-1 antitrypsin deficiency, especially those with known AAT gene variants or early signs of liver or lung disease, would be the most relevant candidates.
✕Less likely to help
People without AAT deficiency, those with end-stage irreversible organ damage, or individuals whose specific AAT variants do not respond to proteostasis-targeting drugs may not benefit from this approach.
What this research studies
I have alpha-1 antitrypsin deficiency when my body makes a misfolded AAT protein that can build up in the liver and fail to protect the lungs. Researchers are studying the cell's protein‑folding machinery (including ATF6 and IRE1/XBP1s and chaperones like Hsp70/Grp78 and Hsp90/Grp94) to see if small molecules can reduce harmful AAT aggregation and restore normal protein function. They will test many different genetic AAT variants to find which pathways and compounds work best for each variant using laboratory models and human-derived samples. The ultimate aim is to match treatments to a person’s specific AAT variant to slow or prevent liver and lung damage.
Why it matters
Potential benefit: If successful, this work could lead to medicines that lower liver AAT buildup and preserve lung function for people with AAT deficiency.
How similar studies have gone: Laboratory studies have shown that modulating proteostasis pathways can reduce protein misfolding in models, but using small molecules across diverse human AAT variants for patient benefit remains largely experimental.
Where this research is happening
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Scripps Research Institute, the
La Jolla, United States Active
Researchers
- Principal investigator: Balch, William Edward — Scripps Research Institute, the
- Study coordinator: Balch, William Edward
Related research
Other NIH-funded projects on the same topics.
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Understanding why AAT deficiency harms the liver and how to fix it
A career development program will explore how a genetic liver disease (AAT deficiency) damages liver cells and test ideas that could lead to new treatments for people with ZZ mutations.
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Gene therapy approach to treat Alpha-1 Antitrypsin Deficiency
A gene therapy approach is being developed to treat Alpha-1 Antitrypsin deficiency, a lung disease, with the aim of providing a lasting source of the protective AAT protein.
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Managing Alpha-1-Antitrypsin Deficiency through Protein Pathways
This study is looking at how to better treat Alpha-1-Antitrypsin Deficiency (AATD) by understanding how different gene variations affect the disease and testing new ways to help the body make the AAT protein work better, which could lead to improved treatments for patients like you.
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Creating a new tool to correct a genetic defect causing alpha-1 antitrypsin deficiency.
This study is testing a new way to fix the genetic problem that causes alpha-1 antitrypsin deficiency by using a special tool to edit the gene in your liver, which could lead to better and safer treatments for people with this condition.
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Prediction score for death or lung transplant in emphysema caused by alpha-1 antitrypsin deficiency
This study tests a new prediction tool to identify people with emphysema due to alpha-1-antitrypsin deficiency who are at high risk of death or needing a lung transplant.
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Two weekly doses of Alpha1-Proteinase Inhibitor by injection compared with standard IV dose in alpha-1 antitrypsin deficiency
A 'how it works' test to see if two weekly subcutaneous doses are as safe and help the body process the medicine as well as the standard IV dose for adults with AAT deficiency.
About this research
- This is an active NIH-funded research project — typically early-stage science, not a clinical trial accepting patient enrollment.
- Some NIH-funded labs run parallel clinical studies or seek volunteers for related work. To check, contact the principal investigator or institution listed above.
- For full project details, budget, and progress reports, visit the official NIH RePORTER page.