Multiple Sclerosis

Multiple sclerosis (MS) is a central nervous system autoimmune disease that targets and destroys the myelin sheath that surrounds axons as well as the axons themselves.

The most common form of MS is relapsing-remitting MS, where symptoms can appear for days or weeks, then resolve spontaneously. In secondary progressive MS, pre-existing neurological deficits worsen over time due to the cumulative damage to the axon and myelin sheath. Primary progressive MS affects 15% of MS patients, where there are gradually worsening symptoms from the start, with no relapses. MS can start between 10 to 80 years of age, but onset is typically between 20 and 40 years, the mean being 32 years of age.

Symptoms are broad as the disease can target any area in the central nervous system, such as the brain and spinal cord. Brain lesions, namely in the cerebrum, are the most common, but manifest relatively few symptoms. As the cerebral lesions are clinically silent, they are usually identified via MRI. Spinal cord lesions will have the patient present with sensory or motor dysfunction. Hemiparesis or paraparesis may occur depending on the level and areas within the spinal cord affected. Relapsing MS is filled with periods where symptoms initially manifest over days, then worsen over weeks, then subside over weeks and months. Progressive MS is most commonly seen as an advancing myelopathy that presents gradually with asymmetric leg weakness, ataxia, and spasticity.

Diagnosis is crucial at the early stages of MS, so that appropriate therapies can be implemented to reduce the impact of the disease. However, there are no pathognomonic findings in MS. Instead, a diagnosis is made after weighing evidence in support of or against MS as the entity. An MRI may be helpful when showing typical lesions, but a diagnosis of MS cannot depend on MRI alone.

The cause of MS remains unknown, although it is likely that the impetus may be multifactorial. There is no cure for MS, but technological advances have allowed for the development of disease-modifying therapies (DMTs) that slow the progression of the disease. Current DMTs are preventive and focus on the early inflammatory phase of the disease by aiming to inhibit disease activity. Treatment at the early stage is crucial in that cumulative and irreversible tissue damage will reduce the benefit of DMTs.

MS therapies are expensive, costing nearly $50,000 annually. The market is sizable, even when only considering the American market, where 400,000 are suffering from MS. This results in a market size of approximately $20 billion. There is a need for therapies that can be used in relapsing and progressive MS, especially since progressive MS is much more difficult to treat.

Animal Models of Multiple Sclerosis

Pharma Models LLC offers a variety of different models of multiple sclerosis. The most commonly used are induced models using peptides or toxins. The Experimental Autoimmune Encephalomyelitis (EAE) model is considered the most widely used in medical research. EAE is a spectrum of neurological disorders that can be induced in mice via immunization with CNS antigens. For mice, the most popular model is the MOG-induced EAE, where a MOG peptide (MOG35-55) is used to induce disease in C57BL/6 mice.

For the cuprizone mouse model, C57BL/6 mice are fed chow mixed with cuprizone for a specified period of time in order to induce demyelination and oligodendrocyte death. Both acute and chronic paradigms can be produced, depending on how long the cuprizone is to be given. This model is ideal for examining demyelination and remyelination as well as studying factors affecting oligodendrocyte turnover and myelin repair.

MOG-induced EAE model of Multiple Sclerosis

The MOG-induced EAE model is very commonly used due to the ability of a peptide called MOG35-55 is able to induce EAE in C57BL/6 mice. The mice are immunized by having the peptide injected subcutaneously and equally across three sites on the shaved backs of the mice. On days 0 and 2, pertussis toxin is injected intraperitoneally relative to immunization. The mice first experience an acute phase where weight loss is observed. The phase will be present at variable times depending on whether the disease is relapsing/remitting, monophasic, or chronic/progressive. Mice will reach a peak of the acute phase, then can experience remission, recovery, or can develop chronic disease.

Cuprizone model of Multiple Sclerosis

The cuprizone model is another commonly used model for MS. In this model, male C57BL/6 mice at 6 to 9 weeks of age are fed a chow mixed with cuprizone, a copper chelating agent. Typically by the third week of feeding, demyelination can be observed in the corpus callosum. Demyelination reaches a maximum at 5 or 6 weeks of cuprizone treatment. Remyelination can then be studied by switching the mice over to normal chow. Remyelination reaches completion 3 to 5 weeks after the cuprizone is taken away. The cuprizone targets mature oligodendrocytes, which make up the myelin sheath of the axons in the central nervous system (CNS).

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