AATD Clinical Trial
Official title:
Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) - Alpha-1 Protocol
This project is designed to examine the interaction between the microflora in the lower
airway and the concentration of a serum protein called alpha-1 antitrypsin. The hypothesis
is that alpha-1 antitrypsin impacts the diversity and content of the lower airway
microflora, resulting in a less inflammatory airway.
The Specific Aims are:
1. To compare the lower respiratory tract microbiome and virome population diversity and
content in age and GOLD stage matched PiZZ individuals not receiving augmentation
therapy, PiZZ individuals on augmentation therapy, PiMZ individuals not receiving
augmentation therapy, and PiMM individuals with chronic obstructive pulmonary disease
(COPD).
2. Determine correlations between bronchoalveolar lavage (BAL) and peripheral blood gene
expression patterns and patterns in lung microbial and viral populations across all
cohorts.
3. Correlate the presence or absence of computed tomography (CT) bronchiectasis and
bronchiolectasis with patterns in the microbiome population diversity and content.
4. To identify and define novel molecular phenotypes of Alpha-1 Antitrypsin Deficiency
(AATD) based on computational integration of clinical, transcriptomic, and microbiome
data.
Alpha-1 Antitrypsin Deficiency (AATD, Alpha-1) is a genetic condition that predisposes to
early onset pulmonary emphysema and airways obstruction, often indistinguishable from usual
smoker's chronic obstructive pulmonary disease (COPD). Prominent features of AATD COPD
include basilar predominant panacinar emphysema, frequent radiographic bronchiectasis, and a
prominent interaction with environmental factors that influence clinical disease phenotypes.
Alpha-1 antitrypsin (AAT) is the most abundant serum and lung antiprotease and has a variety
of biologic activities that influence lung homeostasis. Prominent among these are roles in
neutrophil elastase inhibition, antiprotease activities against cathepsins, involvement in
the complement cascade, and interaction with toll receptors.
Since the effects of AAT on lung homeostasis remain poorly understood, the Alpha-1 protocol
for the Genomic Research in AAT Deficiency and Sarcoidosis (GRADS) grant (hereafter called
GRADS Alpha-1 protocol) is designed to investigate the overarching hypothesis that alpha-1
antitrypsin (AAT) impacts the diversity and content of the lower airway microflora,
resulting in a less inflammatory airway.
Since the risk for bronchiectasis, COPD severity as measured by GOLD stage, and emphysema
extent is proportional to the serum AAT concentration, comparison between different
genotypes of AAT replete and deficient populations will provide data to determine if the
diversity and content of the lower airway microflora influence the risk of COPD in the AATD
population. The AATD population is selected because these individuals have a measurable
interaction with environmental burdens22,28 and may be key to garnering an understanding of
the interplay between this important anti-protease, airways and lower lung inflammation,
peripheral blood gene expression, and radiologic and clinical phenotypes of COPD.
The GRADS Alpha-1 Study is a prospective cross-sectional cohort study that will enroll
approximately 200 participants at seven clinical centers with a total of nine recruitment
locations over two years. An ancillary application to SPIROMICS will request data from 50
PiMM subjects, all (estimate 10) PiMZ subjects, and any (estimate 1) PiZZ subjects. The
remainder of the participants (N=~139) will be recruited through GRADS Alpha-1 centers. All
participants will have two study-related visits (Baseline and Bronchoscopy). During the
study visits, clinic staff will conduct physical examinations and tests, collect biological
specimens, and administer a series of questionnaires to study participants. Participants
could also receive a telephone call to determine the final status of any adverse event, 1
month after study conclusion.
;
Observational Model: Case-Only, Time Perspective: Cross-Sectional
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