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

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Brief Title

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

Official Title

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

Brief 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 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.

Study Type


Primary Outcome

Epigenetic signature of specific inflammation-associated histone modifications from CD14+ macrophages

Secondary Outcome

 Epigenetically regulated genomic profile of AATD in AM


Alpha 1-Antitrypsin Deficiency

Study Arms / Comparison Groups

 Alpha-1 Antitrypsin
Description:  All AATD patients who will start treatment with alpha-1 antitrypsin augmentation therapy


* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Estimated Enrollment


Start Date

December 2015

Completion Date

November 2020

Primary Completion Date

November 2018

Eligibility Criteria

        Inclusion Criteria:


          -  Age between the ages of 18 and 85

          -  Have a diagnosis of AATD PiZZ or PiMZ established by AAT blood levels and Pi

          -  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:


          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

         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.




18 Years - 85 Years

Accepts Healthy Volunteers

Accepts Healthy Volunteers


Brian P O'Connor, PhD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations



Organization ID


Responsible Party


Study Sponsor

National Jewish Health


 Medical University of South Carolina

Study Sponsor

Brian P O'Connor, PhD, Principal Investigator, National Jewish Health

Verification Date

March 2019