Epigenetic Regulation of Immunity in Alpha-1 Anti-trypsin Deficiency (AATD_Epi)

National Jewish Health

Status: Completed

Conditions: Alpha 1-Antitrypsin Deficiency

Study type: Observational

Funder types: Other

Identifiers

NCT02691611

HS-2939

Details and patient eligibility

About

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.

Full 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.

Enrollment: 39 patients

Sex: All

Ages: 18 to 85 years old

Volunteers: Accepts Healthy Volunteers

Inclusion criteria

AATD

• Age between the ages of 18 and 85
• Have a diagnosis of AATD PiZZ or PiMZ established by AAT blood levels and Pi genotyping
• Are not and have not been on AAT augmentation therapy for the past 6 months
• Able to tolerate and willing to undergo study procedures
• Provide signed informed consent.

Exclusion criteria

AATD

1. History of comorbid condition severe enough to significantly increase risks based on investigator discretion
2. Diagnosis of unstable cardiovascular disease including myocardial infarction in the past 6 weeks, uncontrolled congestive heart failure, or uncontrolled arrhythmia
3. Partial Pressure of Oxygen (PaO2) on room air at rest <50 mmHg or Oxygen saturation (SaO2) on room air at rest <85%
4. Post bronchodilator Forced expiratory volume in one second (FEV1)<30% predicted
5. Use of anticoagulation (patients on warfarin or clopidogrel will be excluded; patients on aspirin alone can be studied even with concurrent use)
6. Dementia or other cognitive dysfunction which in the opinion of the investigator would prevent the participant from consenting to the study or completing study procedures
7. Active pulmonary infection with tuberculosis
8. History of pulmonary embolism in the past 2 years
9. Non-Chronic Obstructive Pulmonary Disease (COPD) obstructive disease (various bronchiolitides, sarcoid, lymphangioleiomyomatosis (LAM), histiocytosis X) or parenchymal lung disease, pulmonary vascular disease, pleural disease, severe kyphoscoliosis, neuromuscular weakness, or other cardiovascular and pulmonary disease, that, in the opinion of the investigator, limit the interpretability of the pulmonary function measures
10. Prior significant difficulties with pulmonary function testing
11. Hypersensitivity to or intolerance of albuterol sulfate or ipratropium bromide or propellants or excipients of the inhalers
12. Hypersensitivity to or intolerance of all drugs required for sedation during conscious sedation bronchoscopy.
13. History of Lung volume reduction surgery, lung resection or bronchoscopic lung volume reduction in any form
14. History of lung or other organ transplant
15. History of large thoracic metal implants (e.g., Implantable cardioverter-defibrillator (AICD) and/or pacemaker) that in the opinion of the investigator limit the interpretability of CT scans
16. Currently taking >=10mg a day/20mg every other day of prednisone or equivalent systemic corticosteroid
17. Currently taking any immunosuppressive agent excepting systemic corticosteroids
18. History of lung cancer or any cancer that spread to multiple locations in the body
19. Current illicit substance abuse, excluding marijuana
20. Known HIV/AIDS infection
21. History of or current exposure to chemotherapy or radiation treatments that, in the opinion of the investigator, limits the interpretability of the pulmonary function measures.
22. Has a BMI > 40 kg/m2 at baseline exam
23. Current or planned pregnancy within the study course.
24. Currently institutionalized (e.g., prisons, long-term care facilities)
25. Have a genotype of PiMZ and ever received intravenous or inhaled alpha-1 augmentation therapy (Alpha-1 Proteinase Inhibitor, A1PI)

Conditional Exclusions

1. Participants who present with an upper respiratory infection or pulmonary exacerbation, either solely participant-identified or that has been clinically treated, in the last six weeks can be rescreened for the study once the six-week window has passed.

2. Participants who present with current use of acute antibiotics or steroids can be rescreened for the study ≥30 days after discontinuing acute antibiotics/steroids.

   This does not apply to participants who are on chronic prednisone therapy of <10 mg per day or <20 mg every other day.

3. Participants who present with a myocardial infarction or eye, chest, or abdominal surgery within six weeks can be rescreened after the six week window has passed.

   Study coordinators should consult with the site principal investigator prior to rescreening these participants.

4. Female participants who present <3 months after giving birth will be asked to reschedule their visit until three months have passed since the birth.

5. Individuals who are PiZZ receiving alpha-1 augmentation therapy (Alpha-1 Proteinase Inhibitor, A1PI) must be off augmentation therapy for >6 months to qualify for stratified enrollment in the PiZZ group not receiving augmentation therapy.

Trial design

39 participants in 2 patient groups

Alpha-1 Antitrypsin

Description:

All AATD patients who will start treatment with alpha-1 antitrypsin augmentation therapy

Healthy Control

Description:

Healthy controls with no lung diseases