Stuart Cook

MD PhD. Targeting regeneration and ageing. Founder Enleofen and VVB Bio. Views my own.

[Stuart Cook @stuartacook1]

Slowing ageing and increasing health-span with anti-IL11 therapy

A 20 min video https://t.co/CkBG5kh0GS

[Stuart Cook @stuartacook1]

Met an “I’m a biotech” guy today. Introduced himself as a ‘serial C-suite’ chap. I thought, what a complete zero-value-add arse. And he was. They mostly are.

[Stuart Cook @stuartacook1]

Therapeutic (small molecule) inhibition of global gp130 signaling improves right ventricular function in a pig model of RV loading.

PAH in humans next?

🙌 https://t.co/bGOwsH93GV

[Stuart Cook @stuartacook1]

Wonderful leaving dinner with Imperial friends and colleagues last night. Thank you for the kind words and the lovely present, which will be put to very good use! 🤗

[Stuart Cook @stuartacook1]

Now perhaps the most replicated target gene for lung fibrosis in multiple POC studies

Four clinical trials in progress:
NCT05331300
NCT05658107
NCT05740475
NCT06612970

All began with PMID: 31554736, just 6 years ago

🚀 https://t.co/WuKctnqcOq

[Stuart Cook @stuartacook1]

Bi-specific
Anti-IL11 + Anti-TSLP
Perhaps for asthma?
Field moving fast https://t.co/LHbKo5Vs4o

[Stuart Cook @stuartacook1]

Clever - non-antibody - ways to inhibit IL11 activity using biased agonist-like modalities to treat fibrotic lung disease:

https://t.co/tal9r4TYmo

And

https://t.co/fw2KDdbkc3

[Stuart Cook @stuartacook1]

Nice
As predicted:
https://t.co/NenxB8HYqY

[Junsu Kang @JunsuKang2]

We are happy to share our new paper. We identified il11 as a regenerative factor to stimulate heart regeneration. However, prolonged il11 treatment causes fibrosis due to persistent activation of the epicardium.
https://t.co/Ic2iNDQd7w

[Stuart Cook @stuartacook1]

🙌
IL11 is directly toxic in cardiac myocytes causing calcium handling disturbance and impaired contraction
Negatively inotropic in vivo
Not just a fibroblast factor
Heart failure target?
🤨
https://t.co/uLdqF2N4mL

[Stuart Cook @stuartacook1]

Timely reminder that the IL-6 (IL-11) trans-signalling idea/field is likely based on an experimental artefact
https://t.co/HXnxebNLQk

[Stuart Cook @stuartacook1]

@TheBHF @DrDeclanORegan @imperialcollege @ImperialMed Whoop! The best.

[Stuart Cook @stuartacook1]

Pssst - its not just IL11 effects on fibroblasts:

“These data show that IL11 inhibits reparative AT2-to-AT1 differentiation in the damaged lung to limit endogenous alveolar regeneration, resulting in fibrotic lung disease”

Damaging EMT, as seen in kidney https://t.co/osJLsAFHAA

[Stuart Cook @stuartacook1]

Nice.

Check out the GWAS hits for menopause at the IL11 locus…

Coincidence?

[Agingdoc🩺Dr David Barzilai🔔MD PhD MS MBA DipABLM @agingdoc1]

Systemic low-dose anti-fibrotic treatment attenuates ovarian aging in the mouse

https://t.co/On0BBMWYlT

[Stuart Cook @stuartacook1]

Trametinib common side effects (BNF):

Abdominal pain; anaemia; constipation; cough; dehydration; diarrhoea; dry mouth; fever; haemorrhage; hypersensitivity; infection; intracranial haemorrhage; lymphoedema; nausea; dyspnea; stomatitis; vomiting, etc https://t.co/lORZ1himfQ

[Stuart Cook @stuartacook1]

💯

We wanted to keep in the clock data, even if pushed to the supplement. We appealed to both the reviewer and [separately] the editor.

If something is truly ‘anti-ageing’ it should affect epigenetic clock, across tissues.

I think it should be a standard biomarker.

[Prof Steve Horvath @prof_horvath]

Sometimes peer review diminishes the quality of an article. Painful example: the authors had to remove their striking epigenetic clock results from the high profile paper titled "Inhibition of IL-11 Signaling Extends Mammalian Healthspan and Lifespan." Fortunately, the peer review files are available online.
https://t.co/IkimNCNLMF

[Michal Tal, PhD @ImmunoFever]

@stuartacook1 @MartinBJensen @aa_widjaja @metapredict @MitoPsychoBio @KSadtler And to keep these thoughts in one🧵: I really think this exciting new understanding of the impacts of IL-11 signaling will help us better understand how Th2-type responses could drive #IACI. There's much metabolic overlap between these illnesses and aging.
https://t.co/NwCtjr2cIV

[Stuart Cook @stuartacook1]

@ydeigin @elonmusk Maybe he could fund some clinical trials! Boy does the field need some help.

[Stuart Cook @stuartacook1]

@ydeigin @PeterDiamandis @SergeyYoung200 @hevolution_f @yurimilner @JeffBezos @sama @brian_armstrong @apollohealthvc Like it!

Needs a visionary person, institution, consortium or even government to fund a pivotal trial. Think non-conventional team = best chance.

Trial design is hard. Small, fundable and approvable, try sarcopenia? Go all out = TAME-like (funding +++)?

[Stuart Cook @stuartacook1]

It is suggested we do more [5 year] mice studies but how about a human trial?

We have an anti-IL11 therapy specifically engineered for human ageing trials at https://t.co/KhbTu36Bz6.

Needs investment, build out, approvable endpoints and not easy +++. But faster to humans…

[David Sinclair @davidasinclair]

25% in mice 🤦‍♂️
https://t.co/OiNfqSLNGH

[Stuart Cook @stuartacook1]

I’ll raise you: How about a clinical trial?

We have engineered a super long acting and potent anti-IL11 for human ageing trials at https://t.co/ioZVt0yypd.

Faster to humans, not another 5 years in mice

Needs investment, build out, approvable endpoints and not easy ++. But..

[Yuri Deigin @ydeigin]

💰 Anyone willing to finance a study combining the latest IL11 inhibition intervention — that was just shown to extend lifespan in mice by 25% — with other interventions with the goal of finding synergistic combinations?

[Stuart Cook @stuartacook1]

@ydeigin @theodorus5 @aubreydegrey We did the Il11ra KO for healthspan and saw similar effects. Not X209 - think PK might be an issue as IL11RA widely expressed and so need multiple dosing for longterm. Not ideal for anti-ageing Rx.