ALPHA 1 ANTITRYPSIN

1991 McElvaney NG, Hubbard RC, Birrer P, Chernick MS, Caplan DB, Frank MM, Crystal RG. Aerosol alpha-1-antitrypsin treatment for cystic fibrosis. Lancet 1991; 337:392-394. [PubMed]
A1-antitrypsin, the main inhibitor of neutrophil elastase, was given in aerosol form to 12 CF patients and found to suppress neutrophil elastase in respiratory lining fluid and restore its anti-neutrophil elastase capacity. Also, the treatment reduced the reversed inhibitory effect of CF epithelial lining fluid on Pseudomonas killing.
Apparently the material used in this trial (purified human plasma a1-antitrypsin - Prolastin, Cutter Biological) was very difficult to obtain in sufficient quantities. A subsequent trial, with a genetically engineered product which eventually became available, disappointingly failed to show significant benefit to patients and was not further developed as a treatment for cystic fibrosis (Martin SL, et al, 2006 below). However, some interest continues in Germany and there may be further developments.

2006 Martin SL, Downey D, Bilton D, Keogan MT, Edgar J, Elborn JS. Recombinant AAT Study Team. Safety and efficacy of recombinant alpha (1)-antitrypsin therapy in cystic fibrosis. Pediatr Pulmonol 2006; 41:177-183. [PubMed]
A previous study had been performed with plasma derived inhibitor (McElvaney et al, 1991 above). In this present study recombinant human ATT was used in a Phase II trial of rAAT at various dose levels. This drug was safe but, disappointingly, had little effect on neutrophil elastase activity and other markers of inflammation. As a result, there was no further work in CF from this group.

However, later a similar trial from Germany (Griese, M. et al, Eur Respir J 2007; 29:240-50. [PubMed] below) did show some reduction of inflammatory markers but no change of respiratory function. These authors suggested that the clear reduction of airway inflammation after ATT treatment may precede pulmonary structural changes; also the ATT deposition region, either bronchial or peripheral, may play a minor role for ATT inhalation in patients with cystic fibrosis. So there may be further developments in relation to CF.

2007 Griese M. Latzin P. Kappler M. Weckerle K. Heinzlmaier T. Bernhardt T. Hartl D. alpha1-Antitrypsin inhalation reduces airway inflammation in cystic fibrosis patients. Eur Resp J 2007; 29:240-250. [PubMed] Although no effect on lung function was observed, the clear reduction of airway inflammation after alpha(1)-antitrypsin treatment may precede pulmonary structural changes. The alpha(1)-antitrypsin deposition region may play a minor role for alpha(1)-antitrypsin inhalation in cystic fibrosis patients.

2008 Griese M. Kappler M. Gaggar A. Hartl D. Inhibition of airway proteases in cystic fibrosis lung disease. [Review] Eur Resp J 2008; 32:783-795. [PubMed] This is a very detailed review of protease inhibition with detailed account of the previous studies up to this time with liberal references.