Recent advances in α-1-antitrypsin deficiency-related lung disease

Figures & data

Figure 1. a-1-antitrypsin structure.

Reproduced with permission from [153].

Figure 2. Complex interaction of pathogenic mechanisms responsible for the development of emphysema in α-1-antitrypsin deficiency.

Polymerization of Z A1AT in the lung (1) leads to local ER stress (2) and establishment of a postinflammatory cascade (3) including increased neutrophil recruitment (4). Lung polymers are also chemoattractants, recruiting and localizing neutrophils further (4). Polymerization in the liver (5) results in serum and lung deficiency (6), causing unopposed neutrophil elastase activity (7) as a result of the recruited neutrophils (4), which in turn can activate other classes of enzymes (8) in addition to other uninhibited serine proteinases. The net result is proteolytic degradation of lung tissue (9), leading to emphysema. In addition, neutrophil elastase-derived peptide (10) and chemokines (11) can amplify the neutrophilic load and accelerate parenchymal damage through further release of proteinases.

A1AT: α-1-antitrypsin; ER: Endoplasmic reticulum; LTB4: Leukotriene B4;

MMP: Matrix metalloproteinase; PR3: Proteinase 3.

Figure 3. Mechanism of lung disease in α-1-antitrypsin deficiency.

Local deficiency of A1AT leads to excess unopposed neutrophil elastase activity (1). Elastase binds to macrophages stimulating release of leukotriene-B4 (2), a potent neutrophil chemotactic mediator. This promotes neutrophil recruitment (3), causing further release of neutrophil elastase and tissue damage (4). In addition, mutant A1AT polymers colocalize with neutrophils, retaining them in the interstitium and promoting further connective tissue degradation (5).

Figure 4. Declining carbon monoxide transfer coefficient (corrected gas transfer) over time, despite relatively stable forced expiratory volume in 1 s, in a patient with α-1-antitrypsin deficiency monitored in the UK registry.

FEV1: Forced expiratory volume in 1 s; KCO: Carbon monoxide transfer coefficient.

Table 1. Current status of validation of selected biomarkers in α-1-antitrypsin deficiency.

Biomarker validation criteria	Biomarker
	Desmosine	Aα-Val360	MMP-9	LTB4
Central to the pathophysiological process	✓	✓	Evidence limited	✓
Relates to disease severity	✓	✓	✓	✓
Is stable and only varies with events known to relate to disease progression	✓	✓
Predicts progression	Increasing levels associated with DLCO decline in small study (11 patients)		✓
Is sensitive to intervention factors that are known to be effective		✓

DLCO: Diffusing capacity of the lungs for carbon monoxide.

Table 2. Clinical trials of gene therapy in α-1-antitrypsin deficiency utilizing different vectors of administration.

Study (year)	Phase	Vector	Administration route	Patients (n)	Main results/conclusions	Ref.
Brigham et al. (2000)	I	Plasmid–cationic liposome complex	Intranasal	5	In the A1AT-transfected nostril nasal lavage fluid:	[135]
					A1AT protein concentration increased, peaking at day 5 (at a third of normal) and returning to baseline by day 14
					IL-8 concentration decreased
Brantly et al. (2006)	I	rAAV2-A1AT	im.	12	One subject (who had not received intravenous augmentation) had detectable subtherapeutic expression of wild-type M-A1AT in the serum (82 nM) 30 days after receiving a dose of 2.1 × 10^13 vg	[136]
					Anti-AAV2 capsid antibodies rose after vector injection (residual M-AAT levels from prior augmentation obscured the results for some patients)
Brantly et al. (2009)	I	rAAV1-A1AT	im.	9	In highest dose cohort receiving 6.0 × 10^13 vg, expression of wild-type M-A1AT seen in two subjects at subtherapeutic levels (0.1% of normal) at 1 year	[137]
					Anti-AAV capsid antibodies developed and IFN-γ ELISpot to AAV1 capsid was positive in all patients by day 14
Flotte et al. (2011)	II	rAAV1-A1AT (herpes simplex virus production method used [138])	im.	9	Interim results:	[139]
					Dose-dependent increase in M-A1AT levels seen
					In highest dose cohort receiving 6 × 10^12 vg/kg serum M-A1AT levels peaked on day 30 with a mean value of 572 nM but this is still subtherapeutic
					Transient creatinine kinase rises seen in higher dose cohorts

ELISpot: Enzyme-linked immunosorbent spot; im.: Intramuscular; rAAV: Recombinant adeno-associated virus; vg: Vector genome.

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Wood AM, Stockley RA. Alpha one antitrypsin deficiency: from gene to treatment. Respiration 74(5), 481–492 (2007).

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Brigham KL, Lane KB, Meyrick B et al. Transfection of nasal mucosa with a normal α1-antitrypsin gene in α1-antitrypsin-deficient subjects: comparison with protein therapy. Hum. Gene Ther. 11(7), 1023–1032 (2000).

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Brantly ML, Spencer LT, Humphries M et al. Phase I trial of intramuscular injection of a recombinant adeno-associated virus serotype 2 αl-antitrypsin (AAT) vector in AAT-deficient adults. Hum. Gene Ther. 17(12), 1177–1186 (2006).

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Brantly ML, Chulay JD, Wang L et al. Sustained transgene expression despite T lymphocyte responses in a clinical trial of rAAV1-AAT gene therapy. Proc. Natl Acad. Sci. USA 106(38), 16363–16368 (2009).

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Chulay JD, Ye GJ, Thomas DL et al. Preclinical evaluation of a recombinant adeno-associated virus vector expressing human α-1 antitrypsin made using a recombinant herpes simplex virus production method. Hum. Gene Ther. 22(2), 155–165 (2011).

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Flotte TR, Trapnell BC, Humphries M et al. Phase 2 clinical trial of a recombinant adeno-associated viral vector expressing a1-antitrypsin: interim results. Hum. Gene Ther. 22(10), 1239–1247 (2011).

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