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Chen et al. Rare Dis Orphan Drugs J 2022;1:15 https://dx.doi.org/10.20517/rdodj.2022.18 Page 3 of 12

slow the progression of emphysema.

However, intravenous augmentation therapy is both expensive and inconvenient for the patient and
remains unavailable in many countries. Research has continued into the pathophysiology of chronic lung
disease including the processes relevant to AATD that suggest alternative strategies may be equally or
potentially more effective in correcting the imbalance that occurs when enzymes such as elastase are
released into an environment where deficient AAT fails to adequately control the enzyme activity exceeding
its physiological role and leading to excessive tissue damage. The mechanism and potential strategies to
enhance protection in AATD are discussed below.

The pathophysiology of emphysema
The proteinase/antiproteinase balance theory
AAT is the most abundant serine proteinase inhibitor in the circulation and plays a major role in the lung
by largely entering the tissues via simple transudation and therefore increases in the presence of local
[19]
inflammation . In healthy individuals, plasma concentration of AAT ranges between 20 to 40 µM resulting
in interstitial concentrations of roughly 80% of that in plasma. The other significant lung inhibitor is the
secretory leukocyte proteinase inhibitor (SLPI) produced by mucous glands and bronchoepithelial cells and
can be secreted basally into the interstitium . Although a reversible inhibitor (unlike AAT, which is
[20]
[21]
irreversible), it is better at protecting elastin from neutrophil elastase than AAT despite being unable to
inhibit Proteinase 3 .
[22]
When the physiological balance between these enzymes (as in AATD) is disturbed, excessive tissue
breakdown occurs as the proteinases will have a longer duration and radius of activity [23,24] . During
neutrophilic inflammation, the neutrophil traffic and elastase load to the lung is increased. In those with
normal AAT, the acute phase response increases AAT production and inflammation increases its
penetration into the lung leading to modulation of inflammation. In AATD, the AAT concentration is too
low at baseline and inflammation is greater than in patients with normal AAT which is associated with a
poor acute phase response . This potentially leads to greater and more persistent tissue damage,
[25]
destruction of elastin, and the development and progression of emphysema.

When AAT-deficient individuals were reported to have increased susceptibility to emphysema
development , researchers quickly recognised the balance between AAT and a destructive enzyme/s
[2]
[3]
(subsequently identified as a feature of neutrophil serine proteinases [9,26] ) was key to maintaining elastin
homeostasis and that emphysema reflected a disturbance in this balance where proteinase activity prevails.
The proteinase/antiproteinase imbalance between AAT and its cognate proteinase is reflected by the
excessive amount and activity of neutrophil elastase in AAT-deficient individuals . Neutrophil elastase
[27]
load in the lung tissue is directly associated with the pathological severity of emphysema . Furthermore,
[28]
the systemic footprint of neutrophil elastase measured as a neutrophil elastase-specific fibrinogen cleavage
product (AaVal360) is significantly higher in AAT-deficient individuals and correlates with the severity and
progression in the early stages of AATD lung disease [29,30] .

In the most prevalent form of AATD, it is the replacement of Glu to Lys at position 342 (hinge loop region)
of the Z variant AAT protein that increases the likelihood of spontaneous polymerisation . As a
[6]
consequence, retention in the liver reduces secretion and hence the plasma and lung concentration,
increasing susceptibility to tissue damage by neutrophil serine proteinases. In addition, polymerised AAT
aggregates can be found in the lung tissue , associated with the accumulation and activation of neutrophils
[31]