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Page 2 of 12 Chen et al. Rare Dis Orphan Drugs J 2022;1:15 https://dx.doi.org/10.20517/rdodj.2022.18

INTRODUCTION
Alpha-1 antitrypsin [(AAT); also known as Serine Protease Inhibitor (SERPIN) family A1] is a polymorphic
[1]
protein expressed in a codominant fashion by 2 alleles on chromosome 14 . It has a modulatory role in
inflammation showing an acute phase response in its manufacture and release from the liver (the major
source of production) and increased diffusion into the affected tissues/organs where it plays a primary role
in protecting tissues from the destructive effect of serine proteinases.

[2]
The importance of this role is indicated by the genetic deficiency first observed in the 1960s . Of the initial
5 cases identified, 3 had severe early onset basal emphysema and subsequent family studies confirmed the
inheritance of the deficiency and the pulmonary association that appeared both spontaneously (with no
[3]
[4]
recognised external risk factors ) but was accelerated by cigarette smoking . Although other clinical
associations such as panniculitis, systemic vasculitis, and liver cirrhosis are also recognised associations, it is
the pulmonary disease that dominates.

Much has been learnt about the pathophysiology of the disease since the early observation of plasma
deficiency. Over 150 variants of the protein have been identified, although most are associated with
apparently “normal” concentrations and function. Deficiency can vary from partial due to heterozygosity of
deficient genes with a normal gene to complete absence of AAT related mostly to point mutations and
[5]
frameshift truncating mutations, although these are especially rare . The majority of clinically relevant
deficient cases are those homozygous for the Z variant which has a point mutation resulting in an amino
acid substitution at position 342 (Glu to Lys) in the mature protein. This substitution can be identified
through the genomic databases as rs28929474-p.Glu366Lys. As a result, this produces a protein that has a
[6-8]
reduced association rate with its target enzymes . This mutation also increases the likelihood of the
protein to polymerise, particularly in the liver, impeding its secretion (by approximately 80%), resulting in
[6-8]
plasma concentrations of ~5 µM .

The most relevant targets for AAT are serine proteinases and especially those stored in and released by
circulating and migrating neutrophils. In the 1970s, the first report on the pulmonary damaging effect of
neutrophil elastase was published . Although this enzyme retains its importance as the direct mediator of
[9]
emphysema and damage to many vital immune functions in the lung, it should be noted that two other
enzymes stored in the same granules in the neutrophil (Proteinase 3 and Cathepsin G) can play similar
damaging roles.

In the 1980s, the link between AAT deficiency (AATD) and emphysema was well established and the logical
way to manage the condition was to enhance the circulating and hence lung concentration of AAT.
Purification of plasma AAT from blood donors proved feasible and intravenous administration raised both
[10]
[11]
the plasma and lung concentrations of AAT to safe and protective levels. Based on these studies, the
United States Food and Drug Administration (FDA) approved weekly intravenous augmentation therapy
for Z homozygous individuals on biochemical efficacy alone.

Because AATD is relatively rare (1 in 1500 to 1 in 5000) related to migration patterns from the Baltic
areas , it was not felt feasible to carry out classical placebo-controlled studies to demonstrate clinical
[12]
efficacy on the physiological progression of emphysema. However, observational studies [13,14] suggested a
benefit. With the advent of highly sensitive quantitative computed tomographic density measurements of
the lung as a direct measure of the emphysema process, the powering of studies to demonstrate the efficacy
of augmentation therapy became feasible. Initial observational [13,14] and placebo-controlled studies [15-17] and a
subsequent adequately powered placebo-controlled study confirmed the ability of intravenous AAT to
[18]