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

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 Biogen

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?

Myelin both enables rapid saltatory conduction and maintains axonal energy homeostasis Nave/Rothstein labs

Remyelination as a neuroprotective strategy

Remyelination – cause or effect? Axons remyelination

Transplantation to rescue remyelination preserves axons Cuprizone X-irradiation Cuprizone X-irradiation OPC transplantation Irvine and Blakemore Brain 2008

Oligodendrocyte ablation results in axon damage PLP CreERT2 DT-A Pohl et al. J Neurosci 2011

Accelerating remyelination increases axon preservation Musc Ach receptor cKO previously newly In oligodendrocytes – myelinated (re)myelinated accelerates remyelination axons axons Mei et al eLife 2016

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?

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

Adult oligodendrocyte precursor cells Nature 1986

Adult OPC activation, recruitment and differentiation drives remyelination

OPCs but not existing oligodendrocytes form new myelin Crawford, Tripathi ….. Richardson and Franklin; Am J Path 2016

Pre-existing oligodendrocytes expressing activated ERK contribute to remyelination Jeffries et al. J Neurosci 2016

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?

Neuropathological analysis of remyelination failure ✗ 30% ✗ 70%

Variability of OPC numbers in MS lesions Boyd et al. Acta Neuropath 2013

Premyelinating oligodendrocytes in MS lesions Chang et al NEJM 2002

Cell biology-based drug screens for remyelination therapies

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?

Using nanofibers to define regulators of myelination Polylactic acid – 2µM diam Marie Bechler

Internode-like sheaths made by oligodendrocytes myelinating PLA fibers

Sheath lengths on fibres are comparable to those in vivo Murtie et al 2007

Oligodendrocytes detect fiber diameter regulation of internode length by fibre thickness

Are all oligodendrocytes the same? Spinal cord oligodendrocytes form longer internodes on PLA fibres

Inhibition may explain failure of remyelination As PSA-NCAM goes down, PSA on unmyelinated axons myelination starts Lubetzki and colleagues (Paris)

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?

Adaptive myelination – experience- dependent myelin plasticity Does adaptive myelination contribute to learning?

Intrinsic and adaptive myelination Bechler at al Curr Biol 2015, Dev Neurobiol 2017

Remyelination generates thin sheaths A. B. `M 1 R 1 x y g ratio = x/y C. myelination R 2 myelin thickness remyelination M 2 axon diameter

Hypothesis – the intrinsic pathway drives remyelination Will remyelin adapt?

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