Plasma Proteinase Inhibitors     

                   It is possible to conclude that, with the exception of antithrombin, the various plasma proteinase inhibitors are intended to function in the extravascular space rather than the intravascular space.   It is my sense that only the development of therapeutic concentrates of antithrombin and α1-antitrypsin has merit.  Antithrombin has potential as a parenteral drug for antithrombin deficiency  but the successful use of an antithrombin product in the larger acquired deficiency market such as sepsis will require the early identification of opportunity and aggressive use of the therapeutic product.   

Parenteral use of  an α1-antitrypsin concentrate has potential for severe α1-antitrypsin deficiency with the caveat that liver fibrosis may be more critical than pulmonary dysfunction.  The larger market for COPD will required the development of local delivery of either protein or gene to the lower lung.    It is possible that gene therapy such as developed by Neurologix for Parkinson's disease (1) would provide insight to device development for this purpose.   The observation that, with the exception of α2-macroglobulin, a substantial amount of every other inhibitor is in the extravascular space; heparin cofactor II and plasminogen activator inhibitor 2 both appear to function only the intravascular space.   C1-inhibitor is an unusual case.   While there is use for the therapeutic concentrate in the treatment of hereditary angioedema, other therapeutic approaches appear to be equally useful.  The potential for the recombinant product in brain ischemic injury is exciting (2) but it is clear that an understanding of the carbohydrate-rich amino terminal domain(3) is required.

                   Redundancy in specificity of inhibition might imply our lack of understanding of function; alternatively a consideration of an extremely thoughtful article by Joe Gally and Gerry Edelman on degeneracy in biological systems (4).  It is likely that the most effective approach to therapeutic intervention via plasma protein proteinase inhibitors other than antithrombin and α1-antitrypsin will involve modulation of gene expression.  I should note that some of the various protein protein proteinase inhibitors may be useful biomarkers.

                   After I had finished and posted the first version of this material, I came across some relevant material in Clinical Mangement of Infections in Immunocompromised Infants and Children (ed. C.C. Patrick, Lippincott, Williams and Wilkins, Philadelphia, PA, USA, 2001).  Althale, Brown, and Furman (Immunomodulation,  Chapter 25, pps. 584-625) note that while anti-TNF antisera or MAB was effective in an animal model of sepsis, clinical trials in human was not successful.   Administration of therapeutic product occurred much earlier (either simultaneous  with or shortly after administration of anti-TNF products) in the animal studies than was possible in the human studies.

                  

1. LeWitt, P.A., Rezai, A.R., Leehey, M.A., et al., AAV2-GAD gene therapy for advanced Parkinson's disease: a double-blind, sham-surgery controlled, randomized trial, Lancet Neurol. 10, 309-319, 2011.

2. Gesuete, R., Storini, C., Fantin, A., et al., Recombinant C1 inhibitor in brain ischemic injury, Ann.Neurol. 66, 332-342, 2009.

3.  Wagnenaar-Bos, I.G. and Hack, C.E., Structure and function of C1-inhibitor, Immunol.Allergy Clin.North Am. 26, 615-532, 2006.

4. Edelman, G.M. and Gally, J.A., Degeneracy and complexity in biological systems, Proc.Natl.Acad.Sci.USA 98, 13763-13768, 2001.