Wednesday, 13 May 2015

Myelin repair

Rittchen S, Boyd A, Burns A, Park J, Fahmy TM, Metcalfe S, Williams A. Myelin repair in vivo is increased by targeting oligodendrocyte precursor cells with nanoparticles encapsulating leukaemia inhibitory factor (LIF).Biomaterials. 2015 Jul;56:78-85. doi: 10.1016/j.biomaterials.2015.03.044

Multiple sclerosis (MS) is a progressive demyelinating disease of the central nervous system (CNS). Many nerve axons are insulated by a myelin sheath and their demyelination not only prevents saltatory electrical signal conduction along the axons but also removes their metabolic support leading to irreversible neurodegeneration, which currently is untreatable. There is much interest in potential therapeutics that promote remyelination and here we explore use of leukaemia inhibitory factor (LIF), a cytokine known to play a key regulatory role in self-tolerant immunity and recently identified as a pro-myelination factor. In this study, we tested a nanoparticle-based strategy for targeted delivery of LIF to oligodendrocyte precursor cells (OPC) to promote their differentiation into mature oligodendrocytes able to repair myelin. Poly(lactic-co-glycolic acid)-based nanoparticles of ∼120 nm diameter were constructed with LIF as cargo (LIF-NP) with surface antibodies against NG-2 chondroitin sulfate proteoglycan, expressed on OPC. In vitro, NG2-targeted LIF-NP bound to OPCs, activated pSTAT-3 signalling and induced OPC differentiation into mature oligodendrocytes. In vivo, using a model of focal CNS demyelination, we show that NG2-targeted LIF-NP increased myelin repair, both at the level of increased number of myelinated axons, and increased thickness of myelin per axon. Potency was high: a single NP dose delivering picomolar quantities of LIF is sufficient to increase remyelination. Impact statement Nanotherapy-based delivery of leukaemia inhibitory factor (LIF) directly to OPCs proved to be highly potent in promoting myelin repair in vivo: this delivery strategy introduces a novel approach to delivering drugs or biologics targeted to myelin repair in diseases such as MS.



Nanoparticles are particles between 1 and 100 nanometers in size. In nanotechnology, a particle is defined as a small object that behaves as a whole unit with respect to its transport and properties. Particles are further classified according to diameter. Ultrafine particles are the same as nanoparticles and between 1 and 100 nanometers in size. Coarse particles cover a range between 2,500 and 10,000 nanometers. Fine particles are sized between 100 and 2,500 nanometer. The surface coating of nanoparticles is crucial to determining their properties. In particular, the surface coating can regulate stability, solubility, and targeting. For biological applications, the surface coating should be polar to give high aqueous solubility and prevent nanoparticle aggregation. Nanoparticles can be linked to biological molecules that can act as address tags, to direct the nanoparticles to specific sites within the body, specific organelles within the cell, or to follow specifically the movement of individual protein or RNA molecules in living cells. Common address tags are monoclonal antibodies, aptamers, streptavidin or peptides. These targeting agents should ideally be covalently linked to the nanoparticle and should be present in a controlled number per nanoparticle. Multivalent nanoparticles, bearing multiple targeting groups, can cluster receptors, which can activate cellular signaling pathways, and give stronger anchoring. Monovalent nanoparticles, bearing a single binding site, avoid clustering and so are preferable for tracking the behaviour of individual proteins.

In this study they targetLeukemia inhibitory factor, or LIF, is an interleukin 6 class cytokine that affects cell growth by inhibiting differentiation however it can influnece oligodendrocyte diffentiation. In this study the nanoparticles bound with LIF have been targeted to NG2 expressing oligodendrocyte precursor cells. They stimulated myelination in a chemical demyelination model will they work in autoimmune demyemyelination we shall see.

CoI: This is a study by TeamG.

24 comments:

  1. Congratulaions Team G - you've upped your game this year (probably in response to my comments on this site). Is there a human trial planned?

    Angery of TW

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    1. It is in development. The technology is safe in humans and the person leading the project is pushing this forward

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    2. More good stuff just submitted :-)

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    3. To be fair it is the work of the company we keep and is down to the hard work of Su Metcalfe

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    4. well done and congrats.

      however, i am just battling a GERD disease excerbated by all the pills I had to take for MS - I wonder if our bodies will cope with a drug cocktail to be taken daily for the rest of our lives.

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    5. Most conditions require cocktails.

      If we start with a induction therapy and it works then no more pills after the start, neuroprotection, then how long do you need to repair for.

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    6. So something like
      Hsct/lemtrada/rituximab
      Phenytoin/testosterone etc
      Then this?
      What about progressive Ms?

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    7. If we believe other published data the LIFnano can be targeted to and inhibit Th17 and promote T reg. and so we can get a double whammy.

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    8. Get on your mouse wheel and speed it up old boy
      And while your at it sort out the charcot project results

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  2. Well done, this sounds really exciting.

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  3. This is really exciting news. Do you have to use this work on the meeces first before human trials? You say that the nanoparticles bound with LIF have been targeted to NG2 expressing OPCs- so I presume you've decided on the targeting agent, and will these nanoparticles only target the cells you want, or could they target other cells? (sorry if these are daft questions)

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    1. They will preferentially target the cells we want although I guess the particles could end up inthe liver and kidney and lungs which are filtering organs.

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    2. The data shows the nano particles either bind their target or stay in the circulation, rather than become trapped in filter organs. Importantly they gradually dissolve ending up as carbon dioxide and water and so they are safe. In fact the particle material is the same as that used for soluble stitches used to close operations. Like stitches, they do their job (release LIF at the target site) then disappear.

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  4. Is Myelin attacked in PPMS which then leads to neurodegeration. Or is it just neurodegeneration ?

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  5. How will these nanoparticles enter CNS?

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    1. Good question,but remember we can get antibodies into CNS and they are massive compared to nanoparticle, however we have some novel approaches that we will be trying..but that is secret at the moment

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    2. After intravenous delivery around 12% of the therapeutic PLGA nanoparticles enter the CNS from the blood.

      But for getting into the CNS, the intra-nasal route is receiving great attention - including for nano therapy and even for stem cells…..a game changer if it proves successful.

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  6. Biogen phase 2 study of anti-LINGO 1 is directly injected into the CNS. Might nanoparticle delivery of anti-LINGO enhance the effect of the drug similar to LIF?

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    1. Dear Steve S......what is your information source in the ongoing trial NCT01864148 there is a dose response using intravenous antibody.

      Good idea about anti-LINGO nano, could be a useful thing although you have probably just sent the idea down the toilet because of public disclosure of the idea, if this approach is not already patented.

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  7. Only just read this thread and want to thank the team for all the hard work, especially Su Metcalfe. It's good to know that development of this approach is in your hands. If you need any volunteers for the trial please say - I'm sure there'll be plenty of us!

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  8. What's the latest news on this study ? thanks.
    Regards as always

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    Replies
    1. "What's the latest news on this study ?"

      No news is bad news in research.

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