MS Models in Drug Discovery Studies
Multiple sclerosis (MS) is an autoimmune neuroinflammatory disease in which demyelination of the central nervous system (CNS) is a hallmark characteristic. There are four major disease categories that have varying degrees of progression and symptoms:
- Relapsing-remitting MS (RRMS), which is characterized by flare-ups and remissions of symptoms
- Secondary progressive MS (SPMS), which may develop in some relapsing-remitting MS patients and is characterized by worsening symptoms with no remissions
- Primary progressive MS (PPMS), where the symptoms progressively get worse with no remissions
- Progressive-relapsing MS (PRMS), which has progressive symptoms from onset with occasional flare-ups
There is no curative therapy currently available for MS; however, a handful of drugs targeting the autoimmune component are used primarily to manage flare-ups. Recently, a new breakthrough therapy (ocrelizumab) was approved for primary progressive MS as well as relapsing-remitting MS, but there is still an unmet clinical need for the more debilitating forms of MS.
Current MS Models
Preclinical studies in animal models typically take two avenues where one avenue focuses on the autoimmune component and the other avenue focuses on the mechanisms of demyelination independent of the autoimmune effects. The EAE (experimental autoimmune encephalomyelitis) series of MS models are widely used to test therapies targeting the inflammation component of MS, while MS models where demyelination is induced by cuprizone, lysolecithin, or ethidium bromide are increasingly being used to test therapeutic candidates. Charles River conducts studies in both inflammation and demyelination models of MS to test the efficacy of novel therapeutics. Interested in learning about other MS animal models?
Charles River offers cuprizone- and lysolecithin-induced rodent models of demyelination to test novel therapies for MS. The cuprizone model uses a validated study design where demyelination is induced followed by a recovery period of remyelination. During the study, motor performance using rotarod tests or fine motor kinematic analysis, anxiety, and cognition are measured at specific intervals along with confirmation histology and IHC studies. Studies using large animal EAE models include MRI analysis and pathological assessment of lesions.
EAE MS models are considered to be standard models for brain inflammation and demyelination studies. At Charles River, validated rat and mouse models of EAE are available for validation studies to test novel MS therapies. The following EAE models are available:
- MOG35-55 EAE in C57BL/6 mice
- SCH EAE in rats
- MOG1-125 EAE in Dark Agouti rats
These MS mouse models have been validated with positive control compounds and drugs including dexamethasone, glatiramer acetate, and fingolimod. The EAE models are used to monitor disease progression and therapeutic response using the following assays:
- Spinal cord and brain pathology monitored via histological techniques and ELISA assays
- SPECT/CT monitoring of inflammation in the brain and spinal cord
- Flow cytometry-based immunophenotyping of peripheral and central nervous system tissues
Frequently Asked Questions (FAQs) about MS Models Validation
What are some of the parameters that change in the cuprizone model of MS?
Along with cognitive disturbance, the following parameters have been observed in cuprizone-induced MS models:
- Increased neuroinflammation measured by SPECT imaging of TSPO, a translocated protein
- Decreased 18F-deoxyglucose consumption by PET imaging after longer exposures to cuprizone
- Decreased immunostaining of myelin basic protein (MBP) in the brain
- Mild neurological consequences, but alterations in the open field testing results
- Changes in specific parameters of fine motor kinematic analysis suggesting gait changes
Do sensory deficits, such as visual impairment, contribute to reduced touchscreen performance versus a true cognitive deficit in cuprizone-induced mice?
Touchscreen testing does rely on visual abilities. However, the majority of cuprizone-induced MS models showed very specific stimulus-oriented behavior and interacted with the stimulus by the end of the touchscreen testing training, excluding the possibility that the cognitive changes were not because the mice were blind. While we cannot exclude the possibility that the vision in cuprizone-induced mice was impaired, visual impairment alone does not sufficiently explain the findings.
Does Charles River offer other MS models based on immune reactions?
Yes, Charles River offers other immunization-based models, such as the injection of myelin oligodendrocyte protein fragments or PLP (proteolytic proteins). These MS models have more severe neurological consequences, but they have not been completely characterized. For example, cognitive impairment has not been tested in these models.
In the fear conditioning paradigm, are freezing or startle responses measured during the training?
Freezing responses indicated as a lack of movement were measured during the training.