Developing effective therapies for progressive forms of Multiple Sclerosis is one of the greatest priorities for the global Multiple Sclerosis community.

What is Multiple Sclerosis?

Multiple Sclerosis (MS) is an inflammatory, chronic and disabling neurological disease characterized by damage to myelin and unsheathing of axons in the central nervous system.  This process causes neurological impairment which very often leads to severe disability. The cause(s) of Multiple Sclerosis remains unknown. Multiple Sclerosis is generally thought to result from an autoimmune process that is triggered in certain individuals with a specific genetic predisposition1.

The Relapsing Remitting form of the disease, which accounts for 85% of cases, is characterized by relapses that either resolve completely or that result in lasting, progressive disability. This Relapsing Remitting form may evolve into a progressive form termed Secondary Progressive Multiple Sclerosis (SPMS). Approximately 15% of Multiple Sclerosis patients will immediately develop a progressive course, without a prior Relapsing Remitting course, this subtype of the disease is known as Primary Progressive Multiple Sclerosis (PPMS)2.

Multiple Sclerosis has been identified as the leading cause of non-traumatic neurological disability in young adults in Western countries3.

 

Sources:

  1. Canto E, et al. Mult Scler. 2018. 24(1):75-79
  2. National Multiple Sclerosis Society. Types of MS. https://www.nationalmssociety.org/What-is-MS/Types-of-MS. Last visited October 2018
  3. Multiple Sclerosis International Federation. Atlas of MS 2013: Mapping multiple sclerosis around the world. http://www.msif.org/wp-content/uploads/2014/09/Atlas-of-MS.pdf. Last visited October 2018

How many people are affected by Multiple Sclerosis?

The Multiple Sclerosis (MS) prevalence rate varies by region and ethnicity, with an estimated mean of 108/100,000 in Europe and 140/100,000 in North America1. The disease typically begins between the 20 and 30 years of age, and affects twice as many women as men1.

Affecting at least 1.3 million people worldwide, Progressive Multiple Sclerosis is a highly disabling disease with a profound physical and emotional impact2,3.

Sources:

  1. Multiple Sclerosis International Federation. Atlas of MS 2013: Mapping multiple sclerosis around the world. http://www.msif.org/wp-content/uploads/2014/09/Atlas-of-MS.pdf. Last visited October 2018
  2. Ontenada D, et al. Lancet. 2017. 389(10076):1357-1366
  3. Holland NJ, et al. Int J MS Care. 2011. 13(2):65-74

How do we classify the different forms of Multiple Sclerosis?

Historically (since 1996), Multiple Sclerosis has been divided into four major forms: three of these forms describe progressive disease while the fourth describes the Relapsing Remitting form (RRMS)1.

 

In 2013, the presence or absence of disease activity was introduced as a descriptor for progressive forms of Multiple Sclerosis, following recommendations from a global committee of Multiple Sclerosis specialists. In this new classification, Progressive Multiple Sclerosis, encompassing both Primary Progressive and Secondary Progressive forms, can be subdivided into four distinct forms1.

 

 

Sources:

  1. Lublin FD, et al. Neurology. 2014. 83(3):278-286

What are the most common symptoms of progressive forms of Multiple Sclerosis?

The clinical characteristics of progressive forms of Multiple Sclerosis are variable as they result from degenerative processes involving different regions of the central nervous system1.

Over many years, symptoms worsen and disabilities accumulate due to continuous and irreversible neurodegeneration.
As a result, Progressive Multiple Sclerosis patients are 6 to 9 times more impaired in walking ability than Relapsing Remitting Multiple Sclerosis (RRMS) patients2.
In patients presenting Relapsing Remitting Multiple Sclerosis, remissions are less complete over time, resulting in loss of nervous function, including walking ability, which occurs approximately 20 years after diagnosis.

 

Sources:

  1. Matthews B. Symptoms and signs of Multiple Sclerosis. In London: Churchill Livingstone (Ed.), Mc Alpine’s Multiple Sclerosis (3rd Ed.). 1998
  2. Holland NJ, et al. Int J MS Care. 2011. 13(2):65-74

What is the burden of Progressive forms of Multiple Sclerosis?

Currently, numerous drugs are available to treat Relapsing Remitting Multiple Sclerosis while therapeutic options for Progressive Multiple Sclerosis patients are rather limited. No current treatment can reverse the progression of disability in progressive forms of Multiple Sclerosis1.

Affecting at least 1.3 million people worldwide, Progressive Multiple Sclerosis remains a highly debilitating disease with a profound physical and emotional impact2,3.
In addition, Progressive Multiple Sclerosis patients are substantially impaired in their ability to walk3 and to work full time4.

Consequently, developing effective therapies for progressive forms of Multiple Sclerosis is one of the greatest priorities for the global Multiple Sclerosis community1.

 

Sources:

  1. Abdelhak A, et al. Front Neurol. 2017. 8:234
  2. Ontenada D, et al. Lancet. 2017. 389(10076):1357-1366
  3. Holland NJ, et al. Int J MS Care. 2011. 13(2):65-74
  4. Bøe Lunde, et al. PloS ONE 9(7):e103317. 2014

The increasing awareness of the role of neurodegeneration in Multiple Sclerosis

While most cases of Multiple Sclerosis begin with a period of inflammatory attacks, neurodegeneration becomes the prominent pathological feature of progressive forms of Multiple Sclerosis. Neurodegeneration is thought to occur early on in the Multiple Sclerosis disease course and is a strong predictor of clinical disability1. Although inflammatory and neurodegenerative events act in concert to induce Multiple Sclerosis-specific brain damage, their relative contributions change during the course of the disease2.

Targeting the neurodegenerative and inflammatory aspects of progressive forms of Multiple Sclerosis is of critical importance; each should be targeted separately2.
Primary Progressive Multiple Sclerosis and Secondary Progressive Multiple Sclerosis are clinically indistinguishable, raising the possibility that neurodegeneration could be based on underlying factors that are independent of inflammation3.

There is a continuing debate about the interplay between inflammation and neurodegeneration. Neurodegeneration may be a separate process from inflammation or a process initially driven by inflammation that becomes self-sustaining4. It is likely that neurodegeneration and inflammation are occurring simultaneously2.
Regardless, scientific researchers agree that neurodegeneration is a key feature of Multiple Sclerosis, defining the course of the disease and patient outcomes, and should be a priority for new treatments5.

 

Sources:

  1. Giovannoni G, et al. Mult Scler Relat Disord. 2016. 9 Suppl 1:S5-S48
  2. Pérez-Cerdá F, et al. Mult Scler Demyelinating Disord. 2016. 1(1):9
  3. Giovannoni G, et al. ACNR. 2012. 12(3):8-11
  4. Louapre C and Lubetski C. Mult Scler. 2015. 21(13):1626-1628
  5. Kremer D, et al. Mult Scler. 2015. 21(5):541-549

Linking progressive forms of Multiple Sclerosis with metabolism approach

In progressive forms of Multiple Sclerosis, mitochondrial injury (e.g. loss of cytochrome c oxidase-I and complex IV, mitochondrial DNA deletions) has been observed in multiple cell types and is recognized as a major factor driving demyelination and neurodegeneration1,2. While the pathological mechanisms that results in mitochondrial injury are not fully resolved yet (e.g. nitric oxide, pro-inflammatory cytokines, glutamate, etc.), the consequences of mitochondrial dysfunction are well understood.

Mitochondria are the energy powerhouses of every cell. The consequences of mitochondrial injury are well known and defined by the term histotoxic hypoxia, which means a state of reduced oxygen consumption and energy failure in conditions of normal blood and oxygen supply2. In chronically demyelinated axons, mitochondria are damaged both functionally – through damage to respiratory chain proteins – and structurally – via damage to mitochondrial DNA. Furthermore, as sodium channels are no longer restricted to Nodes of Ranvier and are instead redistributed all along the chronically demyelinated axon membranes, more sodium ions enter chronically demyelinated axons during action potential propagation3. Consequently, chronically demyelinated axons require more energy to pump out the sodium to allow a second impulse to be propagated and to prevent secondary damage (e.g. calcium entry). The remaining pool of mitochondria that still possess functional respiratory capacity may not be sufficient to compensate for the increase in energy demand occurring in chronically demyelinated axons. This phenomenon has been called “virtual hypoxia”. Indeed, in Multiple Sclerosis tissues, hypoxia-like phenomenon has been observed with the nuclear translocation of HIF-1α4.

In oligodendrocytes, the cells specializing in myelin synthesis, mitochondrial injury can result in the release of apoptosis-inducing factor, ultimately leading to cell death5. In addition, (re)myelination require extensive lipid synthesis6,7. Within the CNS, acetyl-CoA carboxylase 1 (ACC1), primarily expressed in oligodendrocytes8, catalyzes the rate-limiting, committed step in fatty acid biosynthesis: the cytosolic synthesis of malonyl-CoA from acetyl-CoA9,10.
Other metabolic disturbances have been suggested to play a role in Multiple Sclerosis including disturbances in lipid and one-carbon metabolism11.

 

Sources:

  1. Bradl M, et al. Semin Immunopathol. 2009. 31:455-465
  2. Mahad D, et al. Lancet Neurol. 2015. 14(2):183-193
  3. Friese MA, et al. Nat Rev Neurol. 2014. 10(4):225-38
  4. Aboul-Enein F and Lassmann H. Acta Neuropathol. 2005. 109(1):49-55
  5. Veto S, et al. Brain. 2010. 133(Pt 3):822-834
  6. Chrast R, et al. J Lipid Res. 2011. 52(3):419-34
  7. Aggarwal S, et al. Trends Cell Biol. 2011. 21(10):585-93
  8. Sedel F, et al. Neuropharmacology. 2016. 110(Pt B):644-653
  9. Foster DW. J Clin Invest. 2012. 122(6):1958-1959
  10. Tong L. Cell Mol Life Sci. 2013. 70(5):863-891
  11. Levin M, et al. Degener Neurol and Neuromuscul Dis. 2014. 4:49-63