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Thread: Drugs that block structural changes to collagen could prevent lung fibrosis

  1. #1
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    Default Drugs that block structural changes to collagen could prevent lung fibrosis

    Science Daily
    Date: July 3, 2018
    Source: eLife
    Summary:
    A new study provides the first evidence in humans that altered collagen structure affects tissue stiffness during progression of lung fibrosis, suggesting potential approaches for treating the condition.


    Scientists have found that it is the structure of collagen, rather than the amount, that leads to the devastating condition of lung fibrosis, according to a report in the journal eLife.

    The study provides the first evidence in humans that altered collagen structure affects tissue stiffness during progression of lung fibrosis and identifies a potential new target for drugs to prevent the condition.

    It is widely thought that fibrosis occurs when components that hold together a tissue's architecture (called the extracellular matrix (ECM)) build up in the tissue and lead to tissue stiffness. But recently evidence has suggested that this increased stiffness causes the build-up of yet more ECM components, resulting in a cycle that causes more scar tissue.

    "We knew that stiffness is an important factor in the build-up of scar tissue in the lung," explains lead author Mark Jones, NIHR Clinical Lecturer in Respiratory Medicine at the NIHR Southampton Biomedical Research Centre and University of Southampton, UK. "But we didn't understand what specifically causes increased stiffness in diseased human tissue. Given that excessive build-up of collagen is considered a hallmark of fibrosis, we wanted to see whether this molecule has a role in tissue stiffness."

    They started by looking at the biological and mechanical features of lung tissue from people with lung fibrosis and compared this to healthy lung tissue. They found that the lung fibrosis samples were much stiffer than those from healthy people but, surprisingly, had similar levels of collagen.

    However, when they looked at enzymes that give collagen its unique 'cross-linked' structure within the ECM, they found that a family of these enzymes (the LOXL family) was more abundant in the fibrosis samples. This led them to further investigate the types of collagen structures found in the fibrosis samples -- which are broadly grouped into immature and mature collagen cross-links. They found that increased lung tissue stiffness only occurred where there were higher amounts of the mature cross-linked collagen and that, in these samples, the structure of each collagen building block -- or fibril -- was altered. This suggested that it is collagen structure, controlled by the LOXL family, that determines tissue stiffness.

    Having made this discovery, the team tested whether they could alter the structure of collagen by blocking the LOXL enzymes, with a view to preventing lung fibrosis. They tested a compound called PXS-S2A that blocks LOXL-2 and LOXL-3 in lung tissue cells isolated from people with fibrosis. They found that the number of cross-linked collagen molecules declined with an increasing dose of PXS-S2A.The compound also reduced tissue stiffness, even at low concentrations, suggesting that blocking LOXL-2/LOXL-3 could be an effective way to reduce tissue stiffness.

    Finally, they tested the LOXL-2/3 inhibitor in rats with lung fibrosis and found that although there was no effect on total collagen content in the lungs, the treated rats had reduced fibrosis and improved lung function, with no adverse effects.

    "Together, our results identify that treatment approaches which maintain normal collagen architecture may prevent tissue stiffening and limit the mechanisms that drive progressive fibrosis," says Donna Davies, Professor of Respiratory Cell and Molecular Biology at the University of Southampton. "Our findings suggest the need to conduct studies in patients with lung fibrosis to see whether these approaches would be of benefit."
    First treatment in 2007. Pioneering ever since.

    Barbara

  2. #2
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    I find this article of great interest particularly since I have IPF, There are a few companies that are in early stages of testing BUT it seems this inhibitor of LOXL can be compounded for various laboratory tests. Therefore I wonder if some approved drug for a different purpose or supplement can be substituted while waiting for FDA approval and yield similar results? I'm searching but so far no luck.

  3. #3
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    Let us know if you have any luck!
    First treatment in 2007. Pioneering ever since.

    Barbara

  4. #4
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    There seems to be LOXL antibodies that are available from various pharma manufacturers. These LOZL products currently available are not as effective as the enhanced version being tested by a few biotech companies. It seems these biotech companies have improved the outcomes. However, the laboratory results of LOXL antibodies which are available now have impressive results but not as effective as the upcoming therapeutic products being tested.

    The article posted referencing Southhampton University study has been incorporated into a company known as Synairgen and they have partnered with Pharamaxis of Australia. There is also a company by the name of Pharmakea from the US doing similar tests. However, in the interim before these products are approved by the FDS it seems the LOXL antibodies option could be beneficial if supervised by specialist doctor.

    A comparative study conducted by Pharmakea of their enhanced therapeutic product vs the LOXL antibodies referred to as prophylactic product demonstrated very good results in reducing stiff, scarred tissue improving not just slowing progression.

  5. #5
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    Great info Gene. Thank you.

    Something that could reduce stiff, scarred tissue would be a tremendous boon for those suffering from lung disease. Looks like Phase I has been successfully completed for Pharmakea.

    http://markets.businessinsider.com/n...251-1002274359

    Phase II was to begin in early 2018. Haven't heard if it's happening or what.

    http://www.pharmavoice.com/newsrelea...itor-pat-1251/

    Here's a press release for Synairgen -

    https://www.prnewswire.com/news-rele...615847474.html
    First treatment in 2007. Pioneering ever since.

    Barbara

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