Replies to post #6244 on GTC Biotherapeutics (fka GTCB)

[ThomasS]

Interesting application. The possible patient pool may not be large, however.
If it works here, what other areas open up? Where might one find other fibrin clots?

[gym gravity]

Is that rhAT from the goats?

[ghmm]

I heard a talk recently where they said some Japanese docs (or studies I can't recall which) were talking about using anticoagulants to help treat Pulmonary Fibrosis. There were some reasons behind trying it (don't recall from memory) the docs talking about it described it as interesting so it is certainly very early stage and perhaps just hypothesis generating at this point.

As to market opportunity, IMHO, I think Pulmonary Fibrosis is the biggest unmet Orphan disease and even a mediocre treatment will do well.

[floblu14]

>Something different: An animal study in lung injury
where adding heparin to antithrombin helped rather
than hurt. Comments?<

Looks like GTC is one-step ahead of the game -

METHOD OF PREVENTING FIBRIN CLOTS IN PULMONARY TISSUE THROUGH THE USE OF AEROSOLIZED ANTICOAGULANTS

ATIII is a serine proteinase inhibitor (serpin) with anti-coagulant, anti-inflammatory, anti-proliferative and anti-angiogenic properties. The invention features methods of treating a subject having lung injury due to burns and smoke inhalation by administering a synergistic combination of antithrombin III and heparin through pulmonary delivery means.
http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=KR20060130661&F=0

P.S. I'm partially back after having my protruding prostate pulverized -

[biopearl]

Dew, Interesting findings implying a thrombolytic effect of combination therapy. So to speculate: HD ATIII role is in prevention, that is it provides a missing (or at least decreased level of) a factor that prevents thrombin induced conversion of fibrinogen to fibrin thus reducing the likelyhood of clot formation. In the ovine pulmonary burn model presumably clot from release of tissue factors etc is preexistant in the pulmonary tree and then the combination of heparin plus ATIII is administered, implying thrombolysis (and ? antiinflamatory effects). Wonder if we could analogize to heparin resistance in long pump runs in CABG patients where the heparin requires the presence of ATIII to have any anticoagulation effect at all. Am far removed from the world of hematology except for clinical use of heparin in standard situations so I offer this up as speculative based on no "bench" knowlege. Regards, bp

[DewDiligence]

Here’s another preclinical study of AT in lung injury:

http://tinyurl.com/2ef8vn

>>
Antithrombin Inhibits Bronchoalveolar Activation of Coagulation and Limits Lung Injury During Streptococcus Pneumonia In Rats

Crit Care Med. 2007 Oct 23.

Choi G, Hofstra JJ, Roelofs JJ, Rijneveld AW, Bresser P, van der Zee JS, Florquin S, van der Poll T, Levi M, Schultz MJ.

Department of Intensive Care Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

OBJECTIVE: Alveolar fibrin deposition is a hallmark of pneumonia. It has been proposed that natural inhibitors of coagulation, including activated protein C, antithrombin, and tissue factor pathway inhibitor, exert lung-protective effects via anticoagulant and possibly anti-inflammatory pathways. We investigated the role of these natural anticoagulants in Streptococcus pneumoniae pneumonia.

SUBJECTS: Total of 98 male Sprague-Dawley rats.

INTERVENTIONS: Rats were challenged intratracheally with S. pneumoniae (serotype 3, 10 colony forming units), inducing pneumonia. Rats were randomized to intravenous treatment with normal saline, activated protein C, antithrombin, tissue factor pathway inhibitor, heparin, or tissue-type plasminogen activator.

MEASUREMENTS AND MAIN RESULTS: Rats infected with S. pneumoniae had increased thrombin-antithrombin complexes in bronchoalveolar lavage fluid, with decreased levels of antithrombin activity and fibrin degradation products. Administration of activated protein C, antithrombin, and tissue factor pathway inhibitor significantly limited these procoagulant changes. Furthermore, antithrombin treatment resulted in less bacterial outgrowth of S. pneumoniae and less histopathologic damage in lungs.

CONCLUSIONS: Anticoagulant treatment attenuates pulmonary coagulopathy during S. pneumoniae pneumonia. Antithrombin seems to exert significant lung-protective effects in pneumococcal pneumonia in rats.
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