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

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 PiZZ (two Z genes) and 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 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.

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.