Bjorn Again Making us Young for Repair

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No this is not some ABBA sing along but some more work from Bjorn Neumann who has been working with Prof Franklinstein in Cambridge. As you know myelin forming cells and macrophages age and cause myelination to fail. Bjorn found that metformin rejuvenated cells to promote repair.

Today they find the magic switch. The is called c-myc (pronounced Sea-Mick). Abit of c-Myc makes the old young and so we say great lets have some Mick and we can rejuvenate. Increase c-myc and the old becomes young. Drugs please.

However, this is where there is often issue. The genes that make oligodendrocyte precursoe cells make myelin are often ubiquitous (expressed all over the place) and do lots of things in different cells and this means side-effects. This was seen with RXR (gene involved in myelination) treatments (e.g. bexarotene). It looks like it can promote myelination but causes unpleasant side effects. So is c-Myc different. Well no.

I say I have heard of c-myc before . Sorry to say not in a good way. Why? Because c-myc is an oncogene.

An oncogene is a gene that has the potential to cause cancer. In cancer Myc is always expressed. So a drug that is given contniuously to keep Myc expressed could be bad news,

So what does Myc do?

The c-Myc oncogene is a “master regulator” which controls many aspects of cellular growth regulation and cellular metabolism. The metabolic changes which occur in transformed cells (i.e. cancers), many of which are driven by c-Myc overexpression, are necessary to support the increased need for nucleic acids, proteins and lipids necessary for rapid cellular proliferation. At the same time, c-Myc overexpression results in co-ordinated changes in level of expression of gene families which result in increased cellular proliferation. So it is easy to see why it can be useful is remyelination annd it is also evident that it needs to be tinkered with carefully

Myc inhibiton is thus viewed as a promising target for anti-cancer drugs. Unfortunately, Myc possesses several features that render it undruggable such that any anti-cancer drugs for Myc dysregulation will require acting on the protein indirectly, i.e. targeting the mRNA for the protein rather than a small molecule that targets the protein itself

Neumann et al Myc determines the functional age state of oligodendrocyte progenitor cells. Nature Aging 2021; 1:826–837

Like many adult stem cell populations, the capacity of oligodendrocyte progenitor cells (OPCs) to proliferate and differentiate is substantially impaired with aging. Previous work has shown that tissue-wide transient expression of the pluripotency factors Oct4, Sox2, Klf4 and c-Myc extends lifespan and enhances somatic cell function. Here we show that just one of these factors, c-Myc, is sufficient to determine the age state of OPC: c-Myc expression in aged OPCs drives their functional rejuvenation, while its inhibition in neonatal OPCs induces an aged-like phenotype, as determined by in vitro assays and transcriptome analysis. Increasing c-Myc expression in aged OPCs in vivo restores their proliferation and differentiation capacity, thereby enhancing regeneration in an aged central nervous system environment. Our results directly link Myc to cellular activity and cell age state, with implications for understanding regeneration in the context of aging, and provide important insights into the biology of stem cell aging.

This approach will be tested using metformin and a remyelinating drug is a trial in the UK


Safety and efficacy of bexarotene in patients with relapsing-remitting multiple sclerosis (CCMR One): a randomised, double-blind, placebo-controlled, parallel-group, phase 2a study.
Brown JWL, Cunniffe NG, Prados F, Kanber B, Jones JL, Needham E, Georgieva Z, Rog D, Pearson OR, Overell J, MacManus D, Samson RS, Stutters J, Ffrench-Constant C, Gandini Wheeler-Kingshott CAM, Moran C, Flynn PD, Michell AW, Franklin RJM, Chandran S, Altmann DR, Chard DT, Connick P, Coles AJ.Lancet Neurol. 2021 Sep;20(9):709-720. doi: 10.1016/S1474-4422(21)00179-4.PMID: 34418398 Clinical Trial.

Background: Progressive disability in multiple sclerosis occurs because CNS axons degenerate as a late consequence of demyelination. In animals, retinoic acid receptor RXR-gamma agonists promote remyelination. We aimed to assess the safety and efficacy of a non-selective retinoid X receptor agonist in promoting remyelination in people with multiple sclerosis.

Methods: This randomised, double-blind, placebo-controlled, parallel-group, phase 2a trial (CCMR One) recruited patients with relapsing-remitting multiple sclerosis from two centres in the UK. Eligible participants were aged 18-50 years and had been receiving dimethyl fumarate for at least 6 months. Via a web-based system run by an independent statistician, participants were randomly assigned (1:1), by probability-weighted minimisation using four binary factors, to receive 300 mg/m2 of body surface area per day of oral bexarotene or oral placebo for 6 months. Participants, investigators, and outcome assessors were masked to treatment allocation. MRI scans were done at baseline and at 6 months. The primary safety outcome was the number of adverse events and withdrawals attributable to bexarotene. The primary efficacy outcome was the patient-level change in mean lesional magnetisation transfer ratio between baseline and month 6 for lesions that had a baseline magnetisation transfer ratio less than the within-patient median. We analysed the primary safety outcome in the safety population, which comprised participants who received at least one dose of their allocated treatment. We analysed the primary efficacy outcome in the intention-to-treat population, which comprised all patients who completed the study. This study is registered in the ISRCTN Registry, 14265371, and has been completed.

Findings: Between Jan 17, 2017, and May 17, 2019, 52 participants were randomly assigned to receive either bexarotene (n=26) or placebo (n=26). Participants who received bexarotene had a higher mean number of adverse events (6·12 [SD 3·09]; 159 events in total) than did participants who received placebo (1·63 [SD 1·50]; 39 events in total). All bexarotene-treated participants had at least one adverse event, which included central hypothyroidism (n=26 vs none on placebo), hypertriglyceridaemia (n=24 vs none on placebo), rash (n=13 vs one on placebo), and neutropenia (n=10 vs none on placebo). Five (19%) participants on bexarotene and two (8%) on placebo discontinued the study drug due to adverse events. One episode of cholecystitis in a placebo-treated participant was the only serious adverse event. The change in mean lesional magnetisation transfer ratio was not different between the bexarotene group (0·25 percentage units [pu; SD 0·98]) and the placebo group (0·09 pu [0·84]; adjusted bexarotene-placebo difference 0·16 pu, 95% CI -0·39 to 0·71; p=0·55).

Interpretation: We do not recommend the use of bexarotene to treat patients with multiple sclerosis because of its poor tolerability and negative primary efficacy outcome. However, statistically significant effects were seen in some exploratory MRI and electrophysiological analyses, suggesting that other retinoid X receptor agonists might have small biological effects that could be investigated in further studies.

So the study shows ways to find repair such as monitoring optic nerve electrical signals

A delay in the signal (latency) in the optic nerve is a measure of demyelination, Bexarotene reduces this delay hence promoted remyelination

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4 comments

  • The MS Society has pumped in millions (Money, Money, Money) to the centres at Edinburgh and Cambridge over the last decade or so. The centres focused on myelin repair, but nothing has come to Boots the chemist to be prescribed for MSers. The ‘breakthroughs’ announced to date get coverage in the media and my relatives forward them to me saying “great news”. Even if something gets through an early trial the same issues arise ie will a pharma company fund it. Using your ABBA theme I’d say “The Winner Takes it All” – the winners are the research teams in Edinburgh and Cambridge, not MSers. Gimme! Gimme! Gimme! (a remyelination drug that works and can be prescribed to MSers ASAP).

    • Academics can’t bring things to boots the chemist but they can show people what pathways can be targeted.How many drugs have come to covid that do not involve pharma very very few.

      As for central funding, maybe that is why there are scraps for the rest.

    • MS & remyelination aside, am I reading between the lines correctly in that it states that metformin acts on a c-Myc and that can also activate cancer cells? I’m trying to wrap my head around this because my elderly father has been on metformin for quite a long, long time. He’s had issues with some side effects & was at one time switched to another med (for T2d). But as insurance companies reign, he ended up back on Metformin. Eventually he developed a type of nerve cancer (Merkel Cell cancer, stge 2). Should I be pushing at his insurance & Dr then to get him off of Metformin based on his history of Merkel Cell Cancer do you think?

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