Enhancing OPC differentiation in the context of MS The right - - PowerPoint PPT Presentation

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Enhancing OPC differentiation in the context of MS The right - - PowerPoint PPT Presentation

Sep 02, 2023 180 likes •526 views

Enhancing OPC differentiation in the context of MS The right approach? Charles ffrench-Constant MRC Centre for Regenerative Medicine University of Edinburgh Disclosures Advisory work for Bluerock, Roche. Previous collaborations with

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MRC Centre for Regenerative Medicine University of Edinburgh

Charles ffrench-Constant Enhancing OPC differentiation in the context of MS – The right approach?

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Disclosures

  • Advisory work for Bluerock, Roche.
  • Previous collaborations with Biogen
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The logic of remyelination

  • Why is remyelination desirable?
  • How does remyelination occur normally?
  • Where in this process might drugs enhance remyelination?
  • What should be our targets ?
  • Will it work?
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Myelin both enables rapid saltatory conduction and maintains axonal energy homeostasis

Nave/Rothstein labs

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Remyelination as a neuroprotective strategy

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Remyelination – cause or effect?

Axons remyelination

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Transplantation to rescue remyelination preserves axons

Cuprizone X-irradiation Cuprizone X-irradiation OPC transplantation

Irvine and Blakemore Brain 2008

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Oligodendrocyte ablation results in axon damage

PLP CreERT2 DT-A

Pohl et al. J Neurosci 2011

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Accelerating remyelination increases axon preservation

Musc Ach receptor cKO In oligodendrocytes – accelerates remyelination previously myelinated axons newly (re)myelinated axons

Mei et al eLife 2016

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The logic of remyelination

  • Why is remyelination desirable?
  • How does remyelination occur normally?
  • Where in this process might drugs enhance remyelination?
  • What should be our targets ?
  • Will it work?
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Oligodendrocyte development

Oligodendrocyte precursors- a type of stem cell Abundant – 5% of neural cells

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Adult oligodendrocyte precursor cells

Nature 1986

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Adult OPC activation, recruitment and differentiation drives remyelination

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OPCs but not existing oligodendrocytes form new myelin

Crawford, Tripathi ….. Richardson and Franklin; Am J Path 2016

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Pre-existing oligodendrocytes expressing activated ERK contribute to remyelination

Jeffries et al. J Neurosci 2016

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The logic of remyelination

  • Why is remyelination desirable?
  • How does remyelination occur normally?
  • Where in this process might drugs enhance remyelination?
  • What should be our targets ?
  • Will it work?
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Neuropathological analysis of remyelination failure

✗ ✗70%

30%

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Variability of OPC numbers in MS lesions

Boyd et al. Acta Neuropath 2013

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Premyelinating oligodendrocytes in MS lesions

Chang et al NEJM 2002

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Cell biology-based drug screens for remyelination therapies

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The logic of remyelination

  • Why is remyelination desirable?
  • How does remyelination occur normally?
  • Where in this process might drugs enhance remyelination?
  • What should be our targets ?
  • Will it work?
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Using nanofibers to define regulators of myelination

Polylactic acid – 2µM diam Marie Bechler

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Internode-like sheaths made by

  • ligodendrocytes myelinating PLA fibers
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Sheath lengths on fibres are comparable to those in vivo

Murtie et al 2007

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Oligodendrocytes detect fiber diameter

regulation of internode length by fibre thickness

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Spinal cord oligodendrocytes form longer internodes on PLA fibres

Are all oligodendrocytes the same?

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Inhibition may explain failure of remyelination

As PSA-NCAM goes down, myelination starts PSA on unmyelinated axons Lubetzki and colleagues (Paris)

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The logic of remyelination

  • Why is remyelination desirable?
  • How does remyelination occur normally?
  • Where in this process might drugs enhance remyelination?
  • What should be our targets ?
  • Will it work?
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Adaptive myelination – experience- dependent myelin plasticity

Does adaptive myelination contribute to learning?

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Intrinsic and adaptive myelination

Bechler at al Curr Biol 2015, Dev Neurobiol 2017

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Remyelination generates thin sheaths

axon diameter myelin thickness remyelination myelination

x y g ratio = x/y

A. B. C. `M1 M2 R2 R1

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Hypothesis – the intrinsic pathway drives remyelination Will remyelin adapt?

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Marie Bechler Andrew Jarjour Matt Swire Rose Owens Monica Kim Susan van Erp Ally Rooney Max Ahmed Steffan Mayerl Gerry Ma Canadian MS Society UK MS Society Wellcome Trust

David Lyons (Edinburgh)