NUZ neurizon therapeutics limited
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Ann: NUZ-001 Promotes Survival in TDP-43 Challenged NSC-34 Cells, page-66

  1. Boffin99
    3,414 Posts.
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    04/05/25
    10:50
    Post #: 78910247

    If TDP-43 is not the primary mechanism of action (MoA) for Monepantel (NUZ-001), then paradoxically — it may actually be more promising for sporadic ALS (sALS). Here's why:

    1. TDP-43 Aggregation ≠ the Whole Story in sALS

    While ~97% of sporadic ALS cases show TDP-43 aggregation, we now understand:

    Aggregation is likely a downstream effect of cellular dysfunction (e.g., stress granules, impaired autophagy, inflammation).

    Simply clearing TDP-43 doesn't fix nuclear depletion, RNA dysregulation, or stress responses.

    Many therapies targeting TDP-43 have failed in trials — likely because they miss the core pathological cascade.

    2. Monepantel May Be Targeting the Root Cell Stress Instead

    If Monepantel:

    Enhances autophagy

    Inhibits mTOR (rebalancing metabolism and stress tolerance)

    Reduces neuroinflammation

    Improves mitochondrial quality control

    …then it acts on shared stress-response pathways that:

    Are highly active in sALS

    Precede and exacerbate TDP-43 misprocessing

    Are common to other proteinopathies and age-related degeneration

    This makes it much more likely to benefit a broader sALS population, regardless of TDP-43 status or role.

    3. MoA-Independent of a Single Target = Better for Heterogeneous Disease

    Sporadic ALS is biologically diverse — not all patients will have the same upstream drivers.
    A drug like Monepantel that supports cell survival irrespective of the initiating cause:

    Avoids failure due to mis-targeting

    Can be applied earlier (e.g., in pre-symptomatic or mild disease)

    Makes a stronger case for disease modification rather than just symptomatic relief

    4. Clinical Implication: TDP-43 Independence Broadens Use

    If Monepantel doesn't rely on TDP-43 clearance, then:


    TDP-43-Dependent DrugMonepantelsALSYes, but variable efficacyBroadly applicablefALS (SOD1)Not effectivePotentially effectiveEarly diseaseLimited if no aggregatesEffective via stress modulationCombination useNarrow utilityHighly combinable

    Summary:

    The fact that TDP-43 clearance is not the MoA makes Monepantel more promising for sporadic ALS, because it addresses core, shared pathological processes like autophagy failure, mTOR dysregulation, and cellular stress — not just downstream protein aggregates.
    That means wider clinical utility, stronger neuroprotection, and better odds of meaningful disease modification in the largest ALS population group.

    https://hotcopper.com.au/data/attachments/6978/6978978-c43afb735a1cf548a75251c91f54f818.jpg
    NUZ Price at posting: 14.0¢ Sentiment: Buy Disclosure: Held
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