Multiple sclerosis

We worked with Professor Gavin Giovannoni, one of the top global experts in multiple sclerosis (MS) to help give you a better understanding of the research landscape.


Multiple sclerosis (MS) – an overview

​MS is the most common autoimmune disease of the central nervous system and one of the most common non-traumatic disabling diseases to affect young adults. Over the last 30 years, MS has spread to become a global disease, with incidence of the condition increasing (Dobson et al., 2019). There is currently no single defined cause for the development of MS, though those diagnosed are likely to have a genetic predisposition to the condition. There are several possible variants in the genome which may increase susceptibility to MS, including those within the major histocompatibility (MHC) complex (Haines et al., 1996). Environment and lifestyle may also play a large factor, such as vitamin D exposure and childhood obesity potentially playing a key role in MS onset (Dobson et al., 2019).

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Remyelination, neuroprotection, and neurorestoration

Here, Prof. Giovannoni talks us through some potential therapies in MS and some of the more exciting examples to come through in recent years. 

Opicinumab, a LINGO-1 inhibitor, was one of the first remyelination therapies to make progress (Cadavid et al., 2017) and there is a good selection of biomarkers which can be used to detect remyelination. 

Sodium channel blockers in conjunction with the anticonvulsant phenytoin in optic neuritis can protect the retinal fibre layer and reduce nerve cell loss by 30% (Raftopoulos et al., 2016). 

Following axonal loss, a neuron’s ability to recover is largely reduced, limiting the recovery opportunity for a patient. There are some promising compounds entering clinical trials which may be able to aid recovery. One is a monoclonal antibody in phase 2 trials that targets repulsive guidance molecule A (RGMA); an inhibitor of growth cone formation on synaptogenesis (Demicheva et al., 2015). Blocking this pathway can encourage axonal sprouting. ​


Neurodegeneration

Prof. Giovannoni talks us through neurodegeneration in MS and the unmet needs that still face patients, clinicians, and researchers. The primary event in MS are focal inflammatory lesions, but MS is also associated with the progressive loss of axons and neurons which is thought to lead to the progressive loss of brain volume and ultimately, cognitive impairment. ​

One target for tackling the development of these lesions are microglia, with drugs designed to switch off their activation, such as Bruton tyrosine kinase (BTK) inhibitors, currently in phase 1 and 2 clinical studies. These treatments can also potentially mediate B cell function, another key component to MS pathology as a part of the inflammatory cascade. 


Disease-modifying treatments

Listen to Prof. Giovannoni as he talks us through disease-modifying treatments, de-risking strategy approaches and symptomatic treatments. 

With such a complex disease, affecting each patient differently and each person potentially needing a different approach, the exact pathway to treatment can vary hugely. From certain de-risking strategies, designed to reduce the risk of complications (such as infusion reactions), to the exact approach of treatment as dictated by patient and physician preference, it is a complicated road to a stable treatment regimen. 

Here, Prof. Giovanonni talks us through some potential therapies in MS and some of the more exciting examples to come through in recent years. 
Opicunimab, a LINGO-1 inhibitor, was one of the first remyelination therapies to make progress and there is a good selection of biomarkers which can be used to detect remyelination. 
Sodium channel blockers in conjunction with the anticonvulsant phenytoin in optic neuritis can protect the retinal fibre layer and reduce nerve cell loss by 30% (Raftopoulos et al 2016). 
Following axonal loss, a neuron’s ability to recover is largely reduced, limiting the recovery opportunity for a patient. There are some promising compounds entering clinical trials which may be able to aid recovery. One is a monoclonal antibody in phase 2 trials that targets repulsive guidance molecule A (RGMA); an inhibitor of growth cone formation on synaptogenesis (Demicheva et al 2015). Blocking this pathway can encourage axonal sprouting. 

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Recombinant monoclonal antibodies for MS disease research

Antibody nameClone IDApplicationsSpeciesAbID
Repulsive Guidance Molecule A (RGMA)EP7990(2)WB, ICC/IFMouse, Rat, Humanab169761
Myelin oligodendrocyte glycoprotein (MOG)EP4281WB, IHC-PMouse, Rat, Humanab109746
68kDa Neurofilament/NF-L (NEFL)EPR22035-112WB, IHC-P, IHC-Fr, IP
Mouse, Rat, Humanab223343
MS4A14EPR14020WBMouse, Rat, Humanab182151
GSK3 betaY174WBMouse, Rat, Humanab32391
IL-2 Receptor alpha EPR6452IHC-P, ICC/IFHumanab128955
Acetylcholinesterase (ACHE)EPR18978WB, IHC-P, IHC-FrMouse, Ratab183591
CD20EP459YFlow Cyt, ICC/IF, WB, IP, IHC-PHuman, Monkeyab78237


References

Cadavid D, Balcer L, Galetta S, Aktas O, Ziemssen T, Vanopdenbosch L, Frederiksen J, Skeen M, Jaffe GJ, Butzkueven H, Ziemssen F, Massacesi L, Chai Y, Xu L, Freeman S (2017). Safety and efficacy of opicinumab in acute optic neuritis (RENEW): a randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 189-199.

Demicheva, E., Cui, Y., Schoemaker, H., Mueller, B. K., Demicheva, E., Cui, Y., … Schmidt, M. (2015). Targeting Repulsive Guidance Molecule A to Promote Regeneration and Neuroprotection in Multiple Sclerosis, 1887–1898.

Dobson R, Giovannoni G (2019). Multiple sclerosis - a review. Eur J Neurol. 27-40

Haines JL, Ter-Minassian M, Bazyk A, Gusella JF, Kim DJ, Terwedow H., … Oksenberg JR, (1996).  A complete genomic screen for multiple sclerosis underscores a role for the major histocompatability complex. Nat Genet. 469-71.

Raftopoulos R, Hickman SJ, Toosy A, Sharrack B, Mallik S, Paling D, Altmann DR, Yiannakas MC, Malladi P, Sheridan R, Sarrigiannis PG, Hoggard N, Koltzenburg M, Gandini Wheeler-Kingshott CA, Schmierer K, Giovannoni G, Miller DH, Kapoor R (2016). Phenytoin for neuroprotection in patients with acute optic neuritis: a randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 259-69.




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