Wednesday, 28 June 2017

Blocking NOGO to make nerves

Ineichen BV, Kapitza S, Bleul C, Good N, Plattner PS, Seyedsadr MS, Kaiser J, Schneider MP, Zörner B, Martin R, Linnebank M, Schwab ME.Nogo-A antibodies enhance axonal repair and remyelination in neuro-inflammatory and demyelinating pathology.
Acta Neuropathol. 2017 doi: 10.1007/s00401-017-1745-3

Two hallmarks of chronic multiple sclerosis lesions are the absence of significant spontaneous remyelination and primary as well as secondary neurodegeneration. Both characteristics may be influenced by the presence of inhibitory factors preventing myelin and neuronal repair. We investigated the potential of antibodies against Nogo-A, a well-known inhibitory protein for neuronal growth and plasticity, to enhance neuronal regeneration and remyelination in two animal models of multiple sclerosis. We induced a targeted experimental autoimmune encephalomyelitis (EAE) lesion in the dorsal funiculus of the cervical spinal cord of adult rats resulting in a large drop of skilled forelimb motor functions. We subsequently observed improved recovery of forelimb function after anti-Nogo-A treatment. Anterograde tracing of the corticospinal tract revealed enhanced axonal sprouting and arborisation within the spinal cord gray matter preferentially targeting pre-motor and motor spinal cord laminae on lesion level and above in the anti-Nogo-A-treated animals. An important additional effect of Nogo-A-neutralization was enhanced remyelination observed after lysolecithin-induced demyelination of spinal tracts. Whereas remyelinated fiber numbers in the lesion site were increased several fold, no effect of Nogo-A-inhibition was observed on oligodendrocyte precursor proliferation, migration, or differentiation. Enhancing remyelination and promoting axonal regeneration and plasticity represent important unmet medical needs in multiple sclerosis. Anti-Nogo-A antibodies hold promise as a potential new therapy for multiple sclerosis, in particular during the chronic phase of the disease when neurodegeneration and remyelination failure determine disability evolution

You may have heard of LINGO-1 which is the target for remyelination that has been tried in MS by Biogen. This is related to NOGO (it was a no go signal, i.e. stop signal for nerve grow in the central nervous system). Block it and nerves grow). NOGO is also known as reticulon 4

NOGO variants are derived both from differential splicing and differential promoter usage and encoding different isoforms have been identified. There are three variants: Nogo A, B and C. Nogo-A has two known inhibitory bits including amino-Nogo, at the beginning of the molecule and Nogo-66, which makes up the molecules extracellular loop. Both amino-Nogo and Nogo-66 are involved in inhibitory responses, where amino-Nogo is a strong inhibitor of neurite outgrowth, and Nogo-66 is involved in  destruction of  the growth cone from where nerves grow.

LINGO-1 is a co-receptor that interacts with the ligand-binding Nogo-66 receptor (NogoR) in the Nogo receptor signaling complex.The Nogo receptor complex is formed when Nogo-66 binds to its receptor. LINGO-1 is an essential negative regulator of myelination. It has been implicated in the inhibition of axon regeneration through a ternary complex formed with NgR1/Nogo-66 (ligand-binding subunit) and p75 (signal transducing subunit). NgR1 relies on its co-receptors for transmembrane signalling.The three major myelin-associated inhibitory factors are Nogo, oligodendrocyte myelin glycoprotein, and myelin-associated glycoprotein which all share this receptor complex. 
The inhibitory action is achieved through RhoA-GTP upregulation in response to the presence of MOG, MAG or Nogo-66 in the central nervous system. LINGO-1 also inhibits oligodendrocyte precursor differentiation and myelination, by a mechanism that also involves activation of RhoA, but which apparently does not require p75 or NgR1.

This paper reports that if you block NOGO-A it can have two effects it supports a nerve sprouting effect and it can speed up remyelination. This is great 

However now to burst the bubble abit. "Anti-Nogo-A antibodies hold promise as a potential new therapy for multiple sclerosis".

This study shows what I was saying on saturday about trials in progressive MS. It says that if you do not have a trial system that can detect change than it doesn't matter what your drug does, it won't work.

The suggestion that blocking NOGO is new is not true. It was thought about long before anti-LINGO was thought about as NOGO was discovered first,

Karnezis T, Mandemakers W, McQualter JL, Zheng B, Ho PP, Jordan KA, Murray BM, Barres B, Tessier-Lavigne M, Bernard CC. The neurite outgrowth inhibitor Nogo A is involved in autoimmune-mediated demyelination. Nat Neurosci. 2004;7(7):736-44. 

This paper intimates that blockade of NOGO-A can affect the disease course of EAE, we looked at this in EAE in ABH over a decade ago and it did absolutely nothing...why would it the disease episode in EAE has little to do with nerve loss or demyelination it is inflammatory. 

(Why did we not publish this? it was company sponsored and one experiment does not make a paper). 

Anyway, others also eventually reported it was not much or an immune modulator.

Litwak SA, Payne NL, Campanale N, Ozturk E, Lee JY, Petratos S, Siatskas C, Bakhuraysah M, Bernard CC. Nogo-receptor 1 deficiency has no influence on immune cell repertoire or function during experimental autoimmune encephalomyelitis. PLoS One. 2013;8(12):e82101

So back to the current paper the authors are spinal injury people and so they do their work to show sprouting and so the trial is fit for purpose but if you do EAE a 2-3 week EAE experiment you are looking at three things at once where the immune arm dominates so it is not the right stage of the model to look for repair. So bad trial  design means drug fails.

Away use in spinal injury would be system to test this out. Where is anti-NOGO in development?

Now the real problem anti-LINGO shows us that 99.9% of your drug never gets to the target meaning you load up you subjects with loads of protein, meaning placebo of nothing is flawed. You need a chemical not an antibody.

If blocking the NOGO receptor is going to work wonders, why did this not occur in the anti-LINGO trials in MS? This is because anti-LINGO works on the same cascade and also promotes sprouting in animal models. So let's be realistic. Will anti-NOGO get developed in MS, I think the patent life must be about dead and companies would have done it years ago it they thought it was a winner.

The NOGO system was evolved because it was advantageous not to regrow nerves in the central nervous system. What will be the consequences of blocking the biology? 

I guess you will not have to wait to find out nerve re-growth is being investigated.....but that's another story 

#NewsSpeak: do you want to make a difference?

Do you want to make a difference to world of MS? #NewsSpeak #OffLabel

One of our long running campaigns has been trying to promote access to treatments for pwMS in resource poor environments. For the last 2 years we have been promoting an Essential #OffLabel list of DMTs for resource poor settings. The MS International Federation (MSIF), who represents MS Societies from all over the world, are helping us with this campaign, for example they gave me a platform at their annual CEOs meeting last year to present our campaign.  

The MSIF are now trying to recruit a Head of Research and Access who will lead on the search for improved understanding and treatments for MS and better access to treatments and healthcare. This is global role. So if you are passionate about research, care deeply about MS and feel you have the skills then this may be the job for you. On the plus side it is based in central London; probably the most skilled-up, creative and dynamic city in the world. 

Tuesday, 27 June 2017

Staggeringly profitable business of Science publishing

If you are interested in the publishing process you may want to read this. We have been telling you about the publication process and this article adds to the madness. 

Is the staggeringly profitable business of scientific publishing bad for science? by Stephen Buranyi CLICK Here

In addition to this, the Open access system has turned it all into a bottomless sink. Will it change....not whilst you have things like the REF and Impact factors driving people to publish in these journals. 

The journals have preyed on this so the high impact popular journals have all created open access pay to publish sister journals so when they reject papers they feed them into to the pay to publish journals. 

This has created an open access industry of tripe journals desperate for content......and your cash

Like the saps and Lemmings that we are we have bought into this.
However it is adding millions to the research budget that could be better spent eleswhere.

#EAN2017 & #ClinicSpeak: immune reconstitution therapies

Should access to healthcare, for example HSCT, be equitable? #EAN2017 #ClinicSpeak

As promised the following is my presentation from the Excemed MS Symposium held on Sunday night at the EAN in Amsterdam. I had feedback from several people about how appealing selective immune system depletion followed by reconstitution is as a a treatment strategy for MS. However, the efficacy of all of our licensed DMTs remain a long way off that of what is being reported with HSCT. 

Giovanni Mancardi gave a wonderful meta-analysis in the session on the result of AHSCT and how the safety profile has improved. The most recent mortality is less than 0.3%, i.e. less than 3 in a 1,000 treated patients. I am therefore not surprised that a lot of pwMS who are not concerned about the risks associated AHSCT are frustrated about the lack of access to it as a treatment option. I really hope the NIHR will fund a AHSCT trial in the UK. We need randomised controlled data for AHSCT to become routine; otherwise it will remain a lottery with some pwMS being able to access AHSCT whilst others not being able to access AHSCT. The latter brings up the ethical dilemma about whether of not access to healthcare should be equitable. 

CoI: multiple

Blood NFL as marker of no evidence of disease activity with fingolimod

Plasma neurofilament light chain levels in patients with MS switching from injectable therapies to fingolimod

Fredrik Piehl, Ingrid Kockum, Mohsen Khademi, Kaj Blennow, Jan Lycke, Henrik Zetterberg, Tomas Olsson

Multiple Sclerosis Journal, First Published 19 Jun 2017.doi: 10.1177/1352458517715132


Neurofilament light chain (NFL) is a cerebrospinal fluid (CSF) marker of neuroaxonal damage in multiple sclerosis (MS).

To determine the correlation of NFL in CSF and serum/plasma, and in plasma after switching from injectable MS therapies to fingolimod.

A first cohort consisted of MS patients (n = 39) and neurological disease controls (n = 27) where CSF and plasma/serum had been collected for diagnostic purposes. A second cohort (n = 243) consisted of patients from a post-marketing study of fingolimod. NFL was determined with Single Molecule Array (Simoa™) technology (detection threshold 1.95 pg/mL).

Mean NFL pg/mL (standard deviation (SD)) was 341 (267) and 1475 (2358) in CSF and 8.2 (3.58) and 17.0 (16.94) in serum from controls and MS, respectively. CSF/serum and plasma/serum levels were highly correlated (n = 66, rho = 0.672, p < 0.0001 and n = 16, rho = 0.684, p = 0.009, respectively). In patients starting fingolimod (n = 243), mean NFL pg/mL (SD) in plasma was reduced between baseline (20.4 (10.7)) and at 12 months (13.5 (7.3), p < 3 × 10−6), and levels remained stable at 24 months (13.2 (6.2)).

NFL in serum and CSF are highly correlated and plasma NFL levels decrease after switching to highly effective MS therapy. Blood NFL measurement can be considered as a biomarker for MS therapy response.

Yesterday, I spoke at the European Academy of Neurology (EAN) Congress 2017 in Amsterdam about the utility of neurofilament analysis in neurological disorders. My point was to get across to the audience that neurofilaments as a biomarker was here to stay, but also to make it known that as far as MS management is concerned the goal post is shifting. We are looking to a future in which long-term remission (tantamount to a cure) is achievable, and not simply a woefully inadequate hype that recedes at the end of a conference. So how do the current biological fare in slowing down nerve loss?
I know of two therapies that have already demonstrated this; natalizumab (Tysabri) and fingolimod in the cerebrospinal fluid (CSF). Here the authors present more work on fingolimod, but this time looking at blood neurofilament levels (serum/plasma). The question is whether we are able to substitute blood neurofilament measures effectively for CSF neurofilament measures?
When reading through this paper, a couple of things stand out: 1) the levels in the CSF are ~100-fold higher in the CSF than in the blood, whether it be in PwMS or in controls; 2) the relative ratio's of difference between PwMS and controls in the CSF and blood is ~4 and ~2, respectively based on mean results. In a nutshell, there is more room to detect real changes in neurofilament levels in the CSF than in blood. Well big deal you say, but it matters. Maybe not in a clinical trial with 100+ participants, but at an individual level. If I'm a clinician strongly considering using this test in practice, I'll want to know these relative numbers as I may be basing treatment decisions on these numbers. Interestingly, another group (Disanto et al. JNNP 2016; 87:126-129) previously reported a three fold difference between CIS subjects and controls in serum neurofilaments, but using a different platform (mesoscale, as opposed to Simova used in this study). Maybe a more sensitive method is not all that its cracked up to be?!
All is not lost, as far as swapping from interferons or copaxone to fingolimod there appears to be a significant drop in blood NfL levels at 12 months, which is sustained at 24 months (see figure below). Not all subjects demonstrated a reduction in NfL levels after switching to fingolimod, 49 demonstrated a rise in NFL levels. They tended to be older (see figure below) and had a higher age of onset of disease among other factors. 

There are a lot of archived samples sitting in freezers around the world from clinical trials, now may be the time to start analysing them...I say London is open!

Figure: (a) NfL levels in those switching from injectables to fingolimod sampled at time 0, 12 and 24 months. Mean NfL levels reduced by 34% at 12 months; (b) blood NfL levels correlate with age.