A paper this week in the PNAS formally publishes data from Wyeth researchers on an amyloid-lowering strategy that involves boosting the activity of the plasmin protease. The Alzforum covered previous presentations of this work at two different meetings (see the 2007 Philadelphia meeting coverage and 2006 Madrid meeting coverage). In the meantime, Wyeth has initiated three Phase 1 trials of their clinical candidate, the plasmin activator inhibitor-1 (PAI-1) inhibitor PAZ-417.

The ability of the plasmin protease to degrade amyloid-β has been known for some time (Tucker et al., 2000). Plasmin is activated by tissue plasminogen activator (tPA), and its commonly known function is to degrade fibrin clots. Despite upregulation of tPA in AD brain, plasmin activity remains low because levels of PAI-1 are also elevated (see ARF related news story).

Based on these results, Steve Jacobsen and colleagues at Wyeth in Princeton, New Jersey, have been working to develop CNS-penetrant PAI-1 inhibitors. Their paper describes the activity of their lead inhibitor, PAZ-417, to stimulate Aβ degradation in vitro, and lower brain and plasma Aβ in an AD mouse model. Mice treated with the compound showed improved memory performance in the contextual fear-conditioning test. The paper includes data showing that administration of PAZ-417 to Tg2576 mice 24 hours before hippocampal slice preparation reversed deficits in long-term potentiation seen in the slices. The in vivo activity of the PAI-1 inhibitor depended on its ability to inhibit PAI-1 in the CNS, as a non-brain-penetrant inhibitor did not reduce Aβ or affect behavior.

Activation of the plasmin system raises the fear of bleeding. Preclinical toxicology studies with PAZ-417 in mice, rats, and dogs indicated the compound did not affect bleeding times or show cardiovascular side effects, the authors write. Wyeth is now running three Phase 1 tests of PAZ-417 to establish safety, tolerability, and pharmacokinetics, company representative Michael Lampe told Alzforum. The trials are all listed on ClincalTrials.gov as currently recruiting. The first, NCT00366288, involving 56 healthy young and elderly adults, started in July 2006, and was supposed to wrap up March 2008. A second trial in 40 healthy elderly adults, NCT00663065, began in April 2008 and is scheduled to be completed in September 2008. The third Phase 1 trial, NCT00684710, started in April to recruit 56 healthy Japanese men, and is slated for completion July 2008. There is no data available yet on any of these trials, Lampe said, but he confirmed that the PAI-1 inhibitor continues to be an active clinical program at Wyeth.—Pat McCaffrey.

Reference:
Jacobsen JS, Comery TA, Martone RL, Elokdah H, Crandall DL, Oganesian A, Aschmies S, Kirksey Y, Gonzales C, Xu J, Zhou H, Atchison K, Wagner E, Zaleska MM, Das I, Arias RL, Bard J, Riddell D, Gardell SJ, Abou-Gharbia M, Robichaud A, Magolda R, Vlasuk GP, Bjornsson T, Reinhart PH, Pangalos MN. Enhanced clearance of A{beta} in brain by sustaining the plasmin proteolysis cascade. Proc Natl Acad Sci U S A. 2008 Jun 16. [Epub ahead of print] Abstract

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  1. I have not yet read the full paper in PNAS (awaiting requested PDF), but it is extremely pleasing to find that plasmin is still very much on the AD agenda. We were the first to demonstrate that plasmin cleaves Aβ42 (1) and subsequently to show that its activity was inhibited by aluminum (2). While it would appear that the focus of the current study is on AD therapy, one might assume that it will also inform the discussion concerning AD etiology.

    I congratulate this group on their research and await in anticipation the opportunity to read the full paper.

    References:

    . Plasmin cleaves Abeta42 in vitro and prevents its aggregation into beta-pleated sheet structures. Neuroreport. 2001 Sep 17;12(13):2967-70. PubMed.

    . The degradation of Abeta(25-35) by the serine protease plasmin is inhibited by aluminium. J Alzheimers Dis. 2002 Oct;4(5):357-67. PubMed.

Comments on Primary Papers for this Article

  1. This is a truly exciting study that takes advantage of an Aβ-degrading enzyme to increase Aβ turnover. It is particularly useful as this enzyme can clip the oligomers. It will be very useful to know whether the treatment reduces pro-NGF and increases NGF to also provide neurotrophic support, as pro-NGF can be cleaved by plasmin to its mature form.

    View all comments by Kumar Sambamurti
  2. The Aβ lowering in vivo activity may be due to the very high structural analogy of PAZ-417 to indomethacin and thus γ-secretase modulation.

    The additional phenyl group is tolerated by γ-secretase (see flurbiprofen). Therefore, the observed effect (at the applied concentrations) may in fact be due to γ-secretase inhibition or modulation and not the plasmin cascade. Alternatively, some γ-secretase modulators may operate through the plasmin cascade.

    A reconstituted γ-secretase assay could answer the pending questions.

    View all comments by Boris Schmidt

References

News Citations

  1. Philadelphia: Targets in a Barely Tapped Market Keep Big Pharma Focused on AD
  2. Madrid: Beyond Aβ—Learning, Age, DNA Damage, and Pai-1
  3. Soluble Aβ: Getting a Grip on Its Fate

Paper Citations

  1. . The plasmin system is induced by and degrades amyloid-beta aggregates. J Neurosci. 2000 Jun 1;20(11):3937-46. PubMed.
  2. . Enhanced clearance of Abeta in brain by sustaining the plasmin proteolysis cascade. Proc Natl Acad Sci U S A. 2008 Jun 24;105(25):8754-9. PubMed.

External Citations

  1. NCT00366288
  2. NCT00663065
  3. NCT00684710

Further Reading

Papers

  1. . Enhanced clearance of Abeta in brain by sustaining the plasmin proteolysis cascade. Proc Natl Acad Sci U S A. 2008 Jun 24;105(25):8754-9. PubMed.

News

  1. Philadelphia: Targets in a Barely Tapped Market Keep Big Pharma Focused on AD
  2. Madrid: Beyond Aβ—Learning, Age, DNA Damage, and Pai-1
  3. Soluble Aβ: Getting a Grip on Its Fate

Primary Papers

  1. . Enhanced clearance of Abeta in brain by sustaining the plasmin proteolysis cascade. Proc Natl Acad Sci U S A. 2008 Jun 24;105(25):8754-9. PubMed.