Association of rapamycin treatment with the modulation of purine metabolism…, 2026, Gile, Kaufman, Gottschalk, Roy+

[SNT Gatchaman]

Association of rapamycin treatment with the modulation of purine metabolism, reduced microglial inflammatory responses, improved mitochondrial energy metabolism, and alleviation of fatigue symptoms in ME/CFS subjects: pilot findings from phase-II observational study

Spoiler: Authors

Gile, Brooke; Bulbule, Sarojini; Toriola, Mubaraq A; Ruan, Brian T; Marium, Shabnam; Benko, Anna; Grach, Stephanie; Mueller, Michael; Bateman, Lucinda; Bell, Jennifer; Yellman, Brayden; Berner, Jon; Chheda, Bela; Kaufman, David; Gottschalk, Gunnar; Roy, Avik

BACKGROUND
and rationale In our ongoing phase II observational pilot trial, the compounded formulation of low-dose rapamycin significantly reduced fatigue-related clinical symptoms in ME/CFS subjects. Although the underlying molecular mechanism remains unclear, exploring metabolic pathways involving circulating blood-borne factors is warranted. Recent studies suggest that increased levels of purines may exacerbate oxidative stress in ME/CFS patients. It is not known if rapamycin modulates purine biosynthesis and improves disease symptoms.

METHODS AND RESULTS
To address, we performed a comprehensive LCMS-based quantification of purine biosynthetic intermediates in plasma from responder cohort of ME/CFS participants, both at baseline (BSL) and after 90 days of rapamycin therapy (T3). Notably, differential regulation was observed in the enzymatic conversion of inosine monophosphate (IMP) to xanthosine-5-monophosphate (XMP) and hypoxanthine (HPX) between BSL and T3 samples. Flow cytometry assays on PBMCs confirmed that rapamycin reduces IMP dehydrogenase activity, thereby limiting the conversion of IMP to XMP. Further analyses, including mitochondrial oxidative stress assessments, Seahorse OCR following purine supplementation, and flow cytometry indicate that altered purine levels can impair mitochondrial energy metabolism, and may contribute to inflammatory processes in microglia.

CONCLUSION
Collectively, these findings highlight the therapeutic potential of rapamycin to enhance energy metabolism in patients with ME/CFS.

MAJOR LIMITATIONS
There is no placebo group, and molecular results are somewhat biased to responders.

TRIAL REGISTRATION
CLINICALTRIALS.GOV, NCT06257420. Registered 11 December 2023, https://clinicaltrials.gov/study/NCT06257420.

Web | DOI | PDF | Journal of Translational Medicine | Open Access

 

[Utsikt]

Why are we still doing unblinded trial for ME/CFS outside small pilots?

Overall, 65 participants completed the full BSL-to-T3 protocol. Analysis of the primary endpoints identified that among these completers, 26 participants were classified as responders, 31 as partial responders, and 5 as non-responders.

FUNCAP was a secondary outcome, but if you look at the overall score the changes are negligible:

I don’t understand what the F is.

They say they collected wearable data (including step count) for some, but make up a lot of excuses for why it wasn’t useable:

Wearable device data were collected from a subset of participants; however, the absence of a standardized wearable platform limited meaningful cross- subject comparisons. This limitation was driven in part by budgetary constraints, but reflects broader challenges associated with wearable implementation in ME/CFS research.

Current commercially available devices vary substantially in cost, battery requirements, software architecture, and accessibility to raw physiologic data, limiting inter-device compatibility for advanced metrics such as heart rate variability, sleep architecture, and estimated VO2 max.

In addition, few platforms have been validated specifically for long-term monitoring in ME/CFS or other highly disabled patient populations and are designed to track and promote physical exercise which is contraindicated in ME/CFS [79].

Future studies will require the implementation of a single, validated wearable platform suitable for decentralized clinical monitoring and compatible with the functional limitations of this patient population. Until such approaches become standardized, validated self-reported outcome instruments, including those used in the present study, remain the primary measures of clinical efficacy in ME/CFS research.

They just asked the participants if they had a wearable device so I understand that you can’t compare step counts on a group level when they don’t have the same model. But they could have looked at the step count of each individual and calculated the change, e.g. as a percentage of the baseline.

And there is nothing wrong with giving people a fitbit and telling them to ignore the instructions or turn them off because they are not pacing-compatible. This has been done for years. They are way under $100 each.

Several limitations should be acknowledged in the present investigation. First , the study was not designed as a placebo- controlled trial. Instead, each participant served as their own control, with baseline (BSL) measurements compared to those obtained after treatment at the T3 stage. This approach may introduce certain biases and limit the ability to fully account for placebo effects or other confounding variables.

This is far too weak. It will introduce a lot of biases, as seen in the ritux phase 2 trial that was published more than a decade ago.

Accounting for the expected biases, the results are very underwhelming:

 

[Silip]

Why are we still doing unblinded trial for ME/CFS outside small pilots?

FUNCAP was a secondary outcome, but if you look at the overall score the changes are negligible:
View attachment 33195
I don’t understand what the F is.

They say they collected wearable data (including step count) for some, but make up a lot of excuses for why it wasn’t useable:




They just asked the participants if they had a wearable device so I understand that you can’t compare step counts on a group level when they don’t have the same model. But they could have looked at the step count of each individual and calculated the change, e.g. as a percentage of the baseline.

And there is nothing wrong with giving people a fitbit and telling them to ignore the instructions or turn them off because they are not pacing-compatible. This has been done for years. They are way under $100 each.


This is far too weak. It will introduce a lot of biases, as seen in the ritux phase 2 trial that was published more than a decade ago.

Accounting for the expected biases, the results are very underwhelming:
View attachment 33197View attachment 33198

I agree with everything you say here and have to add that looking at this groups previous papers about Rapamycin I fear that they will (again) frame their study as successful and tout Rapamycin as a highly promising drug regardless of results, let alone the clinical relevance of their findings.

 

[TiredMathematician]

I don’t understand what the F is.

I think it's the test statistic generated by the model on row of that table, which is then used to generate the adjacent p-value.

 

[Trish]

Why are we still doing unblinded trial for ME/CFS outside small pilots?

There is no control group, so who would be blinded?
I agree they should have used at least one objective measure, and the FUNCAP changes look negligible.

 

[Utsikt]

There is no control group, so who would be blinded?
I agree they should have used at least one objective measure, and the FUNCAP changes look negligible.

Ah, I must have meant uncontrolled. But I guess doing a blinded study would necessitate a control group so it comes out to the same.