#35

They use Rapamune.

Protocol is here: Evaluating the effect of rapamycin treatment in Alzheimer’s disease and aging using in vivo imaging: the ERAP phase IIa clinical study protocol 2024

It’s a six-month trial, so weekly might be okay @John_Hemming?

1 Like
#36

Ditto, it’s obviously only a pilot (n=15) but what a great study.

3 Likes
#37

Its the trough that is the issue

#38

Aubrey de Gray has some new data on his multiple intervention trials. Additive effect on females. Complicated for males. I have not listened to the whole thing myself.

Screenshot 2025-02-16 at 7.35.15 PM
Screenshot 2025-02-16 at 7.35.15 PM1920×1200 133 KB

3 Likes
#39

In 2020, Mannick did a trial for a brain-penetrant mTOR inhibitor (RTB101): resTORbio reports interim data from Parkinson’s trial 2020

The multi-centre, randomised, double-blind, placebo-controlled Phase Ib/IIa trial is being conducted to investigate the safety and tolerability of once-weekly RTB101 alone or along with sirolimus.
Participants have been enrolled in three cohorts to date and were treated with 300mg RTB101 alone, 2mg of sirolimus alone, or 300mg of RTB101 plus 2mg of sirolimus.
Meanwhile, 2mg sirolimus, alone or in combination with RTB101, was not detected in the CSF. Enrolment for the combination cohort is ongoing.
resTORbio co-founder and chief medical officer Dr Joan Mannick said: “We are pleased to have observed that RTB101 is well-tolerated and crosses the blood-brain barrier in Parkinson’s disease patients at concentrations that have the potential to induce autophagy, the process by which cells break down toxic misfolded protein aggregates.

Unfortunately, the trial was suspended during the COVID-19 pandemic, the results were never published, and the sponsor (resTORbio) merged with another company (Adicet Bio) in 2020. Mannick left Adicet and Adicet is not working on neurodegenerative diseases anymore: Pipeline | Adicet Bio

Mannick then co-founded Tornado Therapeutics but they’re not working on NDDs either: Team

In the MSA trial they found “no brain mTOR engagement by oral sirolimus up to 6 mg/day”: Neuron-derived extracellular vesicles to examine brain mTOR target engagement with sirolimus in patients with multiple system atrophy 2023. The protocol was the following: https://cdn.clinicaltrials.gov/large-docs/76/NCT03589976/Prot_SAP_000.pdf

We will use sirolimus dosages of 2 mg, 4 mg or 6 mg, once a day based on therapeutic drug monitoring in order to maintain sirolimus drug levels within a FDA-recommended target-range: 5-20 ng/ml. This daily dosage is within the range that is used clinically, and we expect this dose to be well tolerated.

So based on the above, I conclude that rapa does not cross the BBB at doses of 2 to 6 mg daily and serum levels of 5–20 ng/mL. Do you agree @DrFraser @AnUser @John_Hemming @CronosTempi?

Then, the potential benefits seen in the above small study (increased brain volume and CBF) and the ketamine study + the lower risk of AD and PD seen with rapa use in longitudinal studies could be (assuming the studies are correct) outside the brain? Improved BBB integrity? Immunosuppression? Improved cardiovascular function (and indirectly cerebral perfusion?)?

But one of the most bullish rapa experts, Joan Mannick, seems to have abandoned this path: not a good sign?

6 Likes
#40

RTB101 wasn’t a mTORC1 inhibitor according to Kaeberlein (Rapalog companies? - #9 by AnUser), it failed its phase 3 to improve immune response to flu vaccine (Rapalog companies? - #8 by AnUser), which is most likely why it merged. IIRC mTORC1 is what people believe provides the longevity benefits in animal models.

I don’t have evidence to the contrary for sure that rapamycin crosses the BBB in significant amounts, and I think the null hypothesis is that rapamycin doesn’t cross the BBB. So I’d agree that it doesn’t. Feels like we’d know pretty easily.

They believe that TOR101 (the lead candidate and different from RTB101) can have effect on NDD, it’s just not the clinical focus for trials, based on historical mTOR trials and success?

image
image1023×577 116 KB

1 Like
#41

I think it either does or does not cross the BBB. I cannot see that any particular dosage would make a threshold change. A proportion will cross or none.

2 Likes
#42

If 6mg daily was not detected in CSF, hard to imagine any dose people are using weekly would get into the brain.

#43

That’s not what Matt K. said. In his 3+ hour long deep dive with Attia he indicated that at least based on mice data, Rapa crosses the BBB if and only if it’s “pushed through” via high and prolonged systemic availability. Apparently it was a combination of size dynamics and hydrophilicity. Needed to be “pushed through,” — their phrase.

With humans you all forget it seems the fact that apoE4 carriers have a defective BBB that’s more penetrable than it has a business to be. Which might explain the discrepancy.

2 Likes
#44

Exactly. And people with PD or MSA tend to have a more porous BBB. So sirolimus most likely does not cross the BBB at all in healthy people.

Could it still be neuroprotective? :man_shrugging:

1 Like
#45

That’s more things to test then and the more conditionals you add the less likely it becomes.
If there isn’t much evidence for rapamycin crossing the BBB in humans, that instead open ups for rapalogs like everolimus already optimized in the lab (though probably for bioavailability), if they cross the BBB.

2 Likes
#46

I don’t think “pushed through” would be a valid analogy.

1 Like
#47

I’m only reporting what they said. Something about the peripheral polarity of the macromolecule getting “stuck” along the inner “tubes” of the BBB but if there was enough flow of it it could get “pushed through.” If someone has a transcript of that interview they could probably look up that phrase to find the exact details. It was one of the most interesting takeaways for me. And again humans have a different BBB from that of mice or rats.

#48

I’ve been thinking about drugs, dementia and the BBB for years now. The one thing to be aware of, is that the BBB is not stable or uniform. With age, the integrity of the BBB declines, and it is naturally more leaky in some phenotypes and conditions. For example, I wondered about the rapamycin study with the various brain volume outcomes that Matt Kaeberlein highlighted. The effect was pronounced in ApoE4 variants, not significant in ApoE3. But I wonder if part of the effect might not be down to the fact that ApoE4 carriers have naturally higher BBB permeability, so more of the drug gets in. And since the BBB tight junctions decline with age, so will drug penetrance increase, so there may be an age dependent effect. But one should think of this not only in direct drug effects, but indirect. For example, lower BBB integrity means more penetration of undesirable molecules, like LPS, which have been implicated in NDDs and the gut-brain axis. Well, perhaps a class of drugs that counteract the effects of, say, LPS in the brain might be then beneficial in such subjects, while not active for those who don’t have BBB impairment. There exist also drugs which address the BBB directly, by enhancing the tightness of the junctions and BBB integrity.

And of course there are drugs which might enable BBB penetration of other drugs which would not cross on their own.

6 Likes
#49

image
image1170×1138 201 KB

image
image1182×646 136 KB

Paper: Loss of glymphatic homeostasis in heart failure 2025

These findings highlight the role of cerebral blood flow as a key regulator of the glymphatic system, suggesting its involvement in the development of brain disorders associated with reduced cerebral blood flow. This study paves the way for future investigations into the effects of cardiovascular diseases on the brain’s clearance mechanisms, which may provide novel insights into the prevention and treatment of cognitive decline.

If rapa improves cerebral blood flow, this could be a potential neuroprotective mechanism?

3 Likes
#50

mTOR1-specific drug is a long way to reality.
We don’t know if the mTOR1-only inhibitor is better for us; maybe holding a ratio of mTOR1/mTOR2 is natura intended for us with rapamycin.
We still don’t know how acetaminophen or metformin mechanistically works but it works for some human conditions wonderfully.
The motive to have a derivative of the original compound (Joan Mannick) is often driven by profit motive more so than science.

3 Likes
#51

The TOR101 safety results in mice and non-human primates is much better than everolimus, though.

1 Like
#52

What is the data, and how is “safe” defined? Also, why don’t we be on Everolimus instead then?

1 Like
#53

See this slide from Mannick:

1 Like
#54
  • Everolimus: thymus shrinkage, lung issues, or eye damage at low doses, starting as low as 0.5–5 mg/kg
  • my goodness, should we be worried about taking rapamycin at all?
  • When would TOR101 be commercially available?
  • Regardless, that’s an incredibly high dosage compared to what we are taking (6 mg weekly).
1 Like