World MS Day


     
World MS Day To mark World MS Day and raise awareness of this disease, we're taking a look at the state of preclinical MS research and efforts to produce more translatable MS animal models.

What is Multiple Sclerosis?

Multiple sclerosis (MS) is a progressive disease of the nervous system, one of the most common neurological disorders and causes of disability in young adults. MS affects 2.3 million people worldwide, including those affected by the disease and their caregivers.

Most people with MS are diagnosed between the ages of 25 and 31, with approximately twice as many women diagnosed than men. The cause of MS is not known and there is no cure, though there are treatments available that can help alleviate symptoms from some forms of MS.

Numerous symptoms affect people with MS including issues with the bladder and bowels, depression, vertigo, emotional, fatigue, itching, pain, sexual dysfunction, spasticity, tremors and walking difficulties1.

Current Treatments for MS

While there is no cure for MS, there are over fifteen approved drugs for treating MS. These drugs fall into several broad categories, including interferon beta-1a, dimethyl fumarate, and three monoclonal antibodies. These drugs reduce the number of relapses, delay progression of disability, and limit new disease activity.

There are at least eight off-label drug treatments for MS that show some success in reducing symptoms.

Treatment for relapses includes high-dose corticosteroids, which reduce inflammation in the central nervous system (CNS). This regimen has no long-term effects on the disease, however.

Preclinical MS Research

MS is a difficult disease to research for many reasons. The cause of MS is unknown, though it is generally believed to be a combination of genetic, immunological, and environmental factors. Because it often takes many years for someone to be diagnosed, and there are so many variables, it has been impossible to determine a specific cause or trigger.

There is no single pattern to the disease, and the course of its progress is unpredictable. The number and position of lesions on a patient's central nervous system does not always correlate with their relapse occurrence or level of disability. There are no definitive tests for the disease.

Despite these difficulties, researchers around the world are teaming up to advance our knowledge of MS. The Progressive MS Alliance, for example, funds two promising research programs2:

  1. Challenge awards: Innovative research to improve understanding of genetic and biologic processes involved in progressive MS, improving clinical trials, and repurposing existing drugs.
  2. Collaborative network awards: Long-term, first-of-its kind multi-national projects stimulating research into the biggest questions facing MS scientists, like speeding up new treatments and the development of new trials.
The Progressive MS Alliance is committed to making progress in understanding and treating MS in these areas:
  • Raise profile and accelerate progress
  • Secure resources and globalize research funding
  • Inspire, galvanize and engage
  • Deliver operational excellence

MS Animal Models

At present, three experimental animal models are the most used for understanding MS pathophysiology3:

  1. Experimental allergic encephalomyelitis (EAE)
  2. Virus models, such as Theiler´s murine encephalomyelitis virus (TMEV)
  3. Toxin models, such as ethidium bromide (EB), lysophosphophatidylcholine (lysolecithin) (LPC), and cuprizone.
These animal models have specific uses for modeling different phases and symptoms of MS. This chart summarizes those models and how they are used in research studies.

Table 1: Summary of the animal models used for developing and testing MS drugs

Animal Model Animal Involved CNS area Pathology Tested and used in MS patients Therapeutics Agents
RRMS        
Acute EAE Rat, mouse, rabbit, primates, marmoset, ship, guinea pigs and goats Brain, spinal cord Demyelination, CD4Th1, Th17 Glatirameracetate, mitoxantrone natalizumab* (69), fingolimod(77-78), beta-interferon (79-80) Teriflunomide (81), alemtuzumab (82), dimethylfumarate(83)
THV Mouse Brain, spinal cord axonal damage, demyelination Fingolimod (90), Dimethyifumarate (92), beta-interferón (91)
MHV Mouse Brain, spinal cord Demyelination, axonal damage, CD8+ None
Adenovirus Rat Focal Demyelination, remyelination, neutrophils BBB breakdown, gliosis None
EB Rat, mouse Focal Demyelination, remyelination, Macrophages, astrocyte depletion beta-interferon (93-94)
LPC Rat, mouse Focal Demyelination, remyelination, Macrophages, CD8/CD4 T cells Fingolimod (95), glatirameracetate (96)
Cuprizone Rat, mouse White matter Demyelination, remyelination, no peripheral recruitment Fingolimod (97), glatiramer acetate (98), dimethylfumarate (99)
Progressive MS        
Chronic EAE Biozzi ABH mouse, Lew Rat, marmoset Brain, spinal cord, cortex Demyelination, axonal and neuronal loss, gliosis. Cortical demyelination Fingolimod (84), glatiramer acetate (85-86), dimethifumarate (75, 87), beta-interferon (88-89)
THV Mouse Brain, spinal cord Demyelination, axonal injury, gliosis None
*Glatiramer acetate, mitoxantrone, and natalizumab were developed in EAE model.


Active Immunization Models of MS

Active immunization models are the most popular mouse models of multiple sclerosis. In the active immunization method, the mouse is immunized using neuro antigens, such as myelin antigens or spinal cord homogenate, which causes development of activated myelin-specific T cells, trafficking of immune cells into the CNS, and direct damage and inflammation in the CNS.

General Benefits and Considerations

  • Quick, relatively easy, and inexpensive
  • Active immunization in Black 6 mice is suitable for compound profiling.
  • Active immunization in SJL mice induces a relapsing/remitting disease phenotype.
  • Antigens for EAE induction include myelin oligodendrocyte glycoprotein (MOG), myelin basic protein (MBP), proteolipid protein (PLP), and spinal cord homogenate.
  • Most protocols call for the use of pertussis toxin (PTX), which increases both the incidence and severity of disease.
  • Disease presents as ascending paralysis and the typical readout is clinical score. Histology may be used to visualize inflammation in the CNS.

Genetically-Modified MS Models

There are two popular, genetically-engineered mouse models of MS in common usage:

  1. The Gfap-luc mouse model offers an additional readout: in vivo imaging of bioluminescence as a marker of neuroinflammation. (Note that the Gfap-luc model on the B6 albino x FVB hybrid background must be used in order to maintain susceptibility to EAE.)
  2. In the Abb KO/Tg HLA-DR4 mouse, the HLA-DR4 allele is associated with the development of autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis. Immunization with a peptide from a proteolipid protein known to bind to HLA-DR4 provokes a strong T cell proliferative response, causing inflammatory lesions in CNS white matter and symptoms of experimental allergic encephalomyelitis (EAE).
A review article by Kipp, 2016 "focuses on progressive experimental autoimmune encephalomyelitis (EAE) models and the cuprizone model [and] summarizes important recent advances in our understanding of the underlying pathology of the cuprizone model4."

As you observe World MS Day, please consider those affected by this disease and our responsibility as scientists to use all diligence and tools available to improve treatments and work towards a cure for MS.

References:
1. World MS Day.
2. Progressive MS Alliance.
3. Silva, B. and Ferrari, C., Animal experimental models for understanding and treating Multiple Sclerosis. SMGroup, 2016.
4. Kipp, M., Nyamoya, S.,Hochstrasser, T. and Amor, S. Multiple sclerosis animal models: a clinical and histopathological perspective Brain Pathology, 2016, Volume 27, Issue 2.

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