Tuesday, 28 June 2016

NewsSpeak: ocrelizumab applications accepted by the FDA and EMA

At last the clock starts ticking for the long ocrelizumab wait #NewsSpeak #Ocrelizumab #MSBlog

"You may have heard already that Roche have finally submitted their RRMS and PPMS dossiers in relation to ocrelizumab to the FDA and EMA (see today's press release below). Ocrelizumab illustrates how long the drug development process takes.  The PPMS ocrelizumab results were made public last year at ECTRIMS and the dossier has only just been submitted approximately 9 months later. The FDA has fast-tracked ocrelizumab so PPMSers in the US should get an answer within 6 months. In Europe the EMA will take up to 12 months and then NICE will have to look at its cos-effectiveness, which typically takes 6-12 months and then post-NICE there is a 3 month delay before NHS England allows us to use it. So in the UK anyone with PPMS hoping to be started on ocrelizumab may have to wait another 2 years, that is assuming is clears all the regulatory and access hurdles. The red tape is unbelievable and then you ask us why academics don't develop drugs?"


CoI: multiple

PoliticalSpeak: MS prevention, or not?

I have finally purchased myself a pair of rose-tinted glasses; just not sure I should be wearing them. #PoliticalSpeak #MSBlog

"I was invited to at attend the MS Society's meeting on 'Developing our MS Society Research Strategy' (see PDF below) and was asked to chaired the Prevention workshop. It was a very enjoyable day and it is very clear that under the leadership of Michelle Mitchell the MS Society are doing things very differently and with focus and energy. The Prevention workshop was really and extension of the Prevention meeting we had last year at Heathrow (see report below). Interestingly when we had the feedback session yesterday afternoon there was a debate on whether or not MS is a preventable disease and whether of not we should be using the term prevention at all. I am not sure how we can avoid it when the MS community voted prevention number 2 on their list of research priorities as part of their James Lind Alliance collaboration. Stating MS is potentially a preventable disease at least allows one to formulate and test hypotheses. The corollary to this is that by stating that MS is not a preventable disease makes formulating and testing hypotheses very difficult."



Top 10 MS research priorities identified

The MS Society, in partnership with the James Lind Alliance, has identified the top 10 research questions that matter most to people affected by MS and healthcare professionals.

After a year of extensively canvassing the views of a wide range of people, over a thousand questions were narrowed down to the top 10:
  1. Which treatments are effective to slow, stop or reverse the accumulation of disability associated with MS?
  2. How can MS be prevented?
  3. Which treatments are effective for fatigue in people with MS?
  4. How can people with MS be best supported to self-manage their condition?
  5. Does early treatment with aggressive disease modifying drugs improve the prognosis for people with MS?
  6. Is Vitamin D supplementation an effective disease modifying treatment for MS?
  7. Which treatments are effective to improve mobility for people with MS?
  8. Which treatments are effective to improve cognition in people with MS?
  9. Which treatments are effective for pain in people with MS?
  10. Is physiotherapy effective in reducing disability in people with MS?


ClinicSpeak: holistic management of multiple sclerosis

New version of MS infographic using the London Underground Map #ClinicSpeak #MSBlog

"The following is the latest version of my infographic depicting MS as a journey on the London Underground. Can any of you spot the changes?"

Continued inflammation in SPMS - the role of antibodies to galectin-3

Mult Scler. 2016 Jun 23. pii: 1352458516655217. [Epub ahead of print]

Identification of galectin-3 as a possible antibody target for secondary progressive multiple sclerosis.

Nishihara H, Shimizu F, Kitagawa T, Yamanaka N, Akada J, Kuramitsu Y, Sano Y, Takeshita Y, Maeda T, Abe M, Koga M, Nakamura K, Kanda T.

Abstract

BACKGROUND:

Recent studies have revealed that the disruption of the blood-brain barrier (BBB) might contribute to the induction of neurodegeneration in the progressive stage of multiple sclerosis (MS).

OBJECTIVE:

We investigated a potential target for the serum auto-antibodies responsible for the BBB impairment in patients with secondary progressive MS (SPMS).

METHODS:

We identified undetermined target antigens in human brain microvascular endothelial cells (BMECs) that reacted with auto-antibodies in sera from SPMS patients using a proteomic approach. In addition, we examined how the identified auto-antibodies compromise the BBB integrity.

RESULTS:

We found that 10 of 11 SPMS sera had auto-antibodies against galectin-3, although the patients with other neurological diseases did not have these antibodies. Downregulation of galectin-3 led to elevated intercellular adhesion molecule-1 (ICAM-1) and phospho-nuclear factor-kappa (NFκ) B p65 expression in the BMECs. Exposure to SPMS patients' sera also increased the protein levels of ICAM-1 and phospho-NFκB p65 in BMECs, but these effects induced by anti-galectin-3 immunoreactivity were canceled by the downregulation of galectin-3.

CONCLUSION:

Galectin-3 is a possible immunological target molecule of the pathogenic auto-antibodies and contributes to the persistent BBB breakdown in patients with SPMS. These antibodies may also serve as a novel biomarker for SPMS.

Discworld (by Terry Pratchett 1948-2015); a large disc resting on the backs of four huge elephants, who in turn are standing on the back of an enormous turtle, the Great A'Tuin.

When it comes to understanding MS there are the known truths, the uncertain truths and the unknown truths - in the Discworld novel Terry Pratchett writes "Nothing has to be true forever. Just for long enough." Therefore, the race to link the dots is an ever consuming appetite in MS research; at the drop of a hat science shifts these truths, ideas become common knowledge and hypotheses, a reality.

In their previous work, the authors demonstrated that antibodies found in the blood of MS subjects leads to a disruption in the barrier that exists between the blood and the brain itself (called the blood brain barrier), as well as increasing the expression of VCAM-1 in the blood vessels; which aids the adhesion of immune cells and their subsequent transfer into the brain (Shimizu F et al. Sera from remitting and secondary progressive multiple sclerosis patients disrupt the blood brain barrier. PLoS ONE 2014; 9:e9872). In this work they report on a novel target (galectin-3) for these antibodies, which may be responsible for disruption in the BBB in those with SPMS (present in 10 of 11 SPMS subjects).  They also demonstrate that removal of these antibodies from the MS blood samples, decreased its effect in up regulating ICAM-1. Therefore, it's possible that anti-galectin-3 antibodies may be responsible for the persistence of BBB damage in SPMS. Of course, the work needs to be replicated in a larger group.

Why is this work interesting and why even blog on it? These and other lines of evidence point to the concept of persistent inflammation in SPMS, including BBB disruption. Immunomodulatory therapies, therefore if used appropriately should get into the brain. This may well be the biggest unknown truth in SPMS land, and now an uncertain truth.

Monday, 27 June 2016

ResearchSpeak: grey matter lesions

Shooting down the CNS plasma cell; can you help? #MSBlog #MSResearch #ResearchSpeak

"One of the hypotheses in relation to progressive MS is that after a period of time inflammation within the brain and spinal cord becomes independent of peripheral mechanisms. In other words it doesn't matter if you switch off T and B cell activation in the periphery, with potent anti-inflammatory drugs, progressive MS will continue unabated. One of the mechanisms that is hypothesised to explain this is immunoglobulin, or antibody, deposition with complement activation within the CNS. The immunoglobulin is produced by the intrathecal (within the coverings of the brain and spinal cord) B cells and plasma cells. Plasma cells in particular are hard nut to crack. They are long-lived and become independent of T cell help. The seem to live in their own niche and churn out antibody. The antibodies are what we refer to oligoclonal bands or OCBs. All the current DMTs and HSCT don't clear the spinal fluid of these antibodies. This is why our group are now exploring add-on treatments to try and get rid of the OCBs; if we get our funding for a trial we may be asking some of you to help by participating in a t rial. Getting rid of intrathecal plasma cells may be easier said that done. However, where there is a will there is a way and where there is biology there must be a mechanism to target; at least that is what we think."

"One of the ways that antibodies cause damage is that when they bind to their target they activate effector proteins called the complement cascade that then does the damage. The study below shows abundant complement activation within MS lesions. Please note that complement can be activated by other mechanisms that are not necessarily related to immunoglobulin; what we are seeing in this study can't simply be extrapolated back to the OCBs and plasma cells. However, this study and other studies provides us with a compelling case to think about additional add-on strategies for treating progressive MS."



Watkins et al. Complement is activated in progressive multiple sclerosis cortical grey matter lesions. J Neuroinflammation. 2016 Jun 22;13(1):161. doi: 10.1186/s12974-016-0611-x.

BACKGROUND: The symptoms of multiple sclerosis (MS) are caused by damage to myelin and nerve cells in the brain and spinal cord. Inflammation is tightly linked with neurodegeneration, and it is the accumulation of neurodegeneration that underlies increasing neurological disability in progressive MS. Determining pathological mechanisms at play in MS grey matter is therefore a key to our understanding of disease progression.

METHODS: We analysed complement expression and activation by immunocytochemistry and in situ hybridisation in frozen or formalin-fixed paraffin-embedded post-mortem tissue blocks from 22 progressive MS cases and made comparisons to inflammatory central nervous system disease and non-neurological disease controls.

RESULTS: Expression of the transcript for C1qA was noted in neurons and the activation fragment and opsonin C3b-labelled neurons and glia in the MS cortical and deep grey matter. The density of immunostained cells positive for the classical complement pathway protein C1q and the alternative complement pathway activation fragment Bb was significantly increased in cortical grey matter lesions in comparison to control grey matter. The number of cells immunostained for the membrane attack complex was elevated in cortical lesions, indicating complement activation to completion. The numbers of classical (C1-inhibitor) and alternative (factor H) pathway regulator-positive cells were unchanged between MS and controls, whilst complement anaphylatoxin receptor-bearing microglia in the MS cortex were found closely apposed to cortical neurons. Complement immunopositive neurons displayed an altered nuclear morphology, indicative of cell stress/damage, supporting our finding of significant neurodegeneration in cortical grey matter lesions.

CONCLUSIONS: Complement is activated in the MS cortical grey matter lesions in areas of elevated numbers of complement receptor-positive microglia and suggests that complement over-activation may contribute to the worsening pathology that underlies the irreversible progression of MS.