p38 Inhibitors Suppress DUX4 Expression of FSHD

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  • #183713
    p38 Inhibitors Suppress DUX4 Expression of FSHD

    Greetings. I’m Mike, have FSHD and hopefully bring some good news!

    So I’m browsing imgur late at night when I should know better and be catching up on sleep, when sitting there on the imgur front page surrounded by cats, dogs, memes and selfies, I see this:

    My friend, who has a daughter with muscular dystrophy, may have found the beginnings of a cure.
    https://imgur.com/gallery/spQSbDY

    You can imagine both my surprise and slight scepticism about seeing a post about FSHD on imgur of all places, and one that is specifically FSHD related!
    After reading it and doing some external research, it appears (although unverified) to be genuine.
    More specifically, the post links to recently published research (August 2019) for DUX4 expression by a team including Fran Sverdrup.

    I’ve searched musculardystrophyuk.org and it seems to be an update to this research which was last updated in April 2017:
    https://www.musculardystrophyuk.org/news/news/early-stage-research-highlights-apabetalone-as-a-potential-treatment-for-fshd/

    The new advances on from what was reported in 2017 seem to be the use of p38α or p38β and now completed animal model testing:

    We previously reported that agonists of the β-2 adrenergic receptor suppress DUX4 expression by activating adenylate cyclase to increase cAMP levels. Efforts to further explore this signaling pathway led to the identification of p38 mitogen-activated protein kinase as a major regulator of DUX4 expression. In vitro experiments demonstrate that clinically advanced p38 inhibitors suppress DUX4 expression in FSHD type 1 and 2 myoblasts and differentiating myocytes in vitro with exquisite potency. Individual small interfering RNA–mediated knockdown of either p38α or p38β suppresses DUX4 expression, demonstrating that each kinase isoform plays a distinct requisite role in activating DUX4

    Finally, p38 inhibitors effectively suppress DUX4 expression in a mouse xenograft model of human FSHD gene regulation. These data support the repurposing of existing clinical p38 inhibitors as potential therapeutics for FSHD. The surprise finding that p38α and p38β isoforms each independently contribute to DUX4 expression offers a unique opportunity to explore the utility of p38 isoform-selective inhibitors to balance efficacy and safety in skeletal muscle. We propose p38 inhibition as a disease-modifying therapeutic strategy for FSHD.

    This sounds like significant progress to me so I thought I’d share it here.

    Have a great christmas all!

    Mike
    Participant
    Posts: 0
    Joined: 09/12/2019
    #183766
    Reply To: p38 Inhibitors Suppress DUX4 Expression of FSHD

    Thank you for highlighting this. Let us hope that it is an early Christmas present for all of us with FHSD.

    Mike

    So many love songs, so little love.

    embayweather embayweather
    Moderator
    Posts: 8
    Joined: 02/11/2015
    #184187
    Reply To: p38 Inhibitors Suppress DUX4 Expression of FSHD

    What are the thoughts when this may be available to the public?

    jsett2205
    Participant
    Posts: 0
    Joined: 29/12/2019
    #184191
    Reply To: p38 Inhibitors Suppress DUX4 Expression of FSHD

    I would imagine that, like all new meds, the time scale is years, if not a decade or so. Much testing has to be done first in the lab, on animals (God forbid) and on volunteers. Then of course if it is proved safe, then there will be the red tape to go through before it is licensed. I remember reading about a ‘cure’ for FHSD about ten years ago, using RNA replacement therapy. Nothing has so far come to fruition, but apparently it was successful in mice.
    Please be assured that progress is being made by the scientists who diligently work on our behalf.

    Mike

    So many love songs, so little love.

    embayweather embayweather
    Moderator
    Posts: 8
    Joined: 02/11/2015
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