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This post is a continuation of exploring the likely first-in-Parkinson's disease modifying effects of Gain Therapeutic's ($GANX) GT-02287. If you want to catch up, click on my profile to find previous posts and the comment discussions.
In doing more research, even if GluSph reduction were the only benefit of GT-02287, that alone could still be disease-modifying. And the more I look into it, the more I think it might be unrealistic to think that the hardened clumps of a-syn aggregation would be clearly reduced in only 90 days, but I could be wrong here. The clinical benefits seen, including improved motor function and things like sense of smell, can be the immediate result of GluSph reductions. To be clear, I think that GT-02287 will affect disease-modification in more ways than just lowering GluSph (as per the many pre-clinical models and our understanding of the importance of Gcase in the cell’s organelles), but these longer-term benefits will take more time than 90 days. This likely includes reducing a-syn aggregates. Animal-to-human time ratios are likely not reliable here. Maybe I’m wrong about the timing and Gain did in fact see reductions in a-syn aggregates, but hypothetically, let’s assume that the only benefit that GT-02287 has within the cell is a strong reduction in GluSph. We now know that it has a strong impact on GluSph.
Elevated GluSph is a key upstream driver of Parkinson’s pathology. It promotes α-syn misfolding, disrupts lysosomal clearance, impairs mitochondria, and creates an accelerating loop of dysfunction. Lowering GluSph like what was demonstrated reduces aggregation pressure, slows new α-syn seeding, stabilizes the pathology, and slows the rate of injury to the neuron. In Gaucher’s it is *the* biggest driver, and as a measure of pathology, the lowering of GluSph directly correlates to disease modification. The reductions in GluSph alone can explain the rapid improvements in UPDRS scores and the anecdotal improvements in smell, gait, and balance. From what I can find, here’s how:
When GluSph drops, studies have shown or suggest:
* Membrane properties normalize
* Vesicle docking and fusion improve
* Neurotransmitter cycling stabilizes
* Synapses start working better
* Mitochondrial function and ATP output improve
This alone can explain rapid clinical improvements—rapid meaning within 90 days. If the ONLY thing that GT-02287 does is greatly reduce GluSph levels & prevent levels from elevating in the first place, and it does this over a period of years (and I can’t see why it wouldn’t), this is enough to slow or stop disease progression, at least in a good chunk of cases. We might have just seen the first evidence of exactly this happening in PD patients. As there are no other therapies that slow or stop progression, this would be a giant win. By the way, they’ll be screening for SAA positive patients for the phase 2 greatly increases the likelihood of success. Not to mention, since they’ll need to do a lumbar puncture for the SAA screening, they can also either screen for elevated GluSph, or create a pre-specified subgroup, for which they are currently batting 100%.
But it is extremely unlikely that properly functioning Gcase will *only* reduce GluSph. We know that functional Gcase has other roles within the cell, and dysfunctional Gcase has other direct adverse effects within the cell. Independent of GluSph reduction, properly functioning Gcase helps relieve ER stress, stabilize lysosomes, improve autophagic flux, enhance mitochondrial function, support vesicle trafficking and synaptic function, reduce future α-syn stress and reduce or prevent aggregation. Returning properly functioning Gcase to all of the cellular areas that need it should result in further long-term clinical improvements or stabilization.
So, as far as clinical improvements go, we might think in terms of 2 phases. Phase 1 is more immediate and in patients who already have elevated levels of GluSph: clinical improvements might be seen as a direct result of GluSph reduction, and say within 2 to 5 months (my guess). Phase 2 would be longer term improvements or stabilization which result from improvements in these other (above) areas in which the dysfunction takes longer to correct, say 5 months to 2 years, depending on the case.
To say it in one sentence, the reduction in GluSph alone is likely disease-modifying if sustained, but it is very unlikely that the benefits of GT-02287 stop there (as per all of the pre-clinical models and what we know of the role that Gcase plays in the neurons).