MD PhD. Targeting regeneration and ageing. Founder Enleofen and VVB Bio. Views my own.
UK or Singapore, depends
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Slowing ageing and increasing health-span with anti-IL11 therapy
A 20 min video piped.video/watch?v=oNc5Mx…
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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.
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Therapeutic (small molecule) inhibition of global gp130 signaling improves right ventricular function in a pig model of RV loading.
PAH in humans next?
🙌 scholar.google.com.sg/schola…
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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! 🤗
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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
🚀 pubmed.ncbi.nlm.nih.gov/3979…
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Bi-specific
Anti-IL11 + Anti-TSLP
Perhaps for asthma?
Field moving fast clinicaltrials.gov/study/NCT…
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Clever - non-antibody - ways to inhibit IL11 activity using biased agonist-like modalities to treat fibrotic lung disease:
sciencedirect.com/science/ar…
And
sciencedirect.com/science/ar…
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Nice
As predicted:
pubmed.ncbi.nlm.nih.gov/3662…
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.
nature.com/articles/s41467-0…
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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?
🤨
academic.oup.com/cardiovascr…
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Timely reminder that the IL-6 (IL-11) trans-signalling idea/field is likely based on an experimental artefact
pubmed.ncbi.nlm.nih.gov/3833…
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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 nature.com/articles/s41467-0…
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Nice.
Check out the GWAS hits for menopause at the IL11 locus…
Coincidence?
Systemic low-dose anti-fibrotic treatment attenuates ovarian aging in the mouse
link.springer.com/article/10…
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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 biorxiv.org/content/10.1101/…
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💯
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.
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.
rdcu.be/dPaL5
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Stuart Cook retweeted
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.
ncbi.nlm.nih.gov/pmc/article…
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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 vvb.bio.
Needs investment, build out, approvable endpoints and not easy +++. But faster to humans…
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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 vvb.bio/.
Faster to humans, not another 5 years in mice
Needs investment, build out, approvable endpoints and not easy ++. But..
💰 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?
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A very interesting question. My best guess = nerves.
In old IL11-EGFP mice there is big signal in skeletal muscle nerve bundles/NMJ (see Supl figs).
Recovery of function with anti-IL11 is > muscle mass effect. So I think innervation is important….
Any thoughts on the muscle mechanism? I can see from our large human data sets that the most variable IL11RA transcript is the low abundance 390aa variant, with the high signal variant (422aa) largely invariant.
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We did epigenetic clock in the mice. Large effect (++). Reviewer 1 made us take it out (despite our protests - see rebuttal at Nature website). Data is shown in our online talks and on BioRxiv (I think). For sure a biomarker of interest for human trials…
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IL11 upregulates PDL1 to promote tumour immune escape
There will be a lot more coming on this
Already heading to clinical trials with Mabwell Therapeutics:
aacrjournals.org/cancerres/a… onlinelibrary.wiley.com/doi/…
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