NCT02691611

Epigenetic Regulation of Immunity in Alpha-1 Anti-trypsin Deficiency

Defining Epigenetic Regulation of Immunity in Alpha-1 Anti-trypsin Deficiency

• Status: Completed
• Phase: —
• Study type: Observational
• Enrollment: 39 (actual)
• Sponsor: National Jewish Health · Academic / Other
• Sex: All
• Age: 18 Years – 85 Years
• Healthy volunteers: Accepted

Summary

The investigators hypothesize that environmentally influenced histone modifications regulate AM mediated inflammation, contributing to a variable clinical course of AATD, and may also influence or be influenced by the activity of AAT augmentation therapy.

Detailed description

The variable natural clinical course of alpha-1 anti-trypsin deficiency (AATD) disease and strong influence of environmental exposures such as smoking, implicate a major role for epigenetic mechanisms in modifying AATD disease penetrance. The goal of this study proposal is to investigate epigenetic regulation of alveolar macrophage (AM) inflammation and function in AATD homozygous alpha 1-protease inhibitor deficiency (PiZZ) (two Z genes) and homozygous alpha 1-protease inhibitor deficiency (PiMZ) (one M and one Z gene) patients. The investigators proposal focuses on epigenetic histone modifications and gene expression specifically in AM. AAT augmentation therapy, which alters disease symptoms, may also modulate AM epigenetics. To identify epigenetic regulation of AM inflammation in AATD in the context of AAT therapy, the investigators will perform and computationally integrate chromatin immunoprecipitation sequencing (ChIP-seq) and RNA-seq data. This will help elucidate the immunomodulatory mechanisms regulating AATD and provide an epigenetic map for diagnosis and targeted treatment. The investigators will test the efficacy of FDA-approved histone modifying drugs, such as Suberoylanilide Hydroxamic Acid (SAHA) and more specific next-generation histone modifiers, such as GSK-J4, to modulate AM AATD-associated activity ex vivo. The goal of this study is to enroll up to a total of 13 AATD cases and 6 healthy controls. All AATD patients will be asked to give a blood sample and/or undergo a bronchoscopy. AATD patients will also be asked to undergo a follow up bronchoscopy and/or blood draw after 6 months if treatment with alpha-1 antitrypsin augmentation therapy is initiated to study the changes in these markers after augmentation therapy.

Conditions

• Alpha 1-Antitrypsin Deficiency

Timeline

• Start date: 2015-12-01
• Primary completion: 2018-11-01
• Completion: 2020-07-01
• First posted: 2016-02-25
• Last updated: 2025-06-06

Locations

1 site across 1 country: United States