Background
One of defining characteristics of multiple sclerosis, particularly in the progressive phase, is the extensive damage that occurs to axons, or nerve fibres, that are found underneath the myelin sheath in the central nervous system. This axonal damage is part of a process called neurodegeneration, and is believed to result in the permanent neurological deficits and disability that are seen in progressive MS. While all of the clinically-approved therapies for MS to date target some aspect of the inflammatory process that triggers disease relapses, combating the neurodegeneration and worsening disability of progressive MS continues to be elusive.
An exciting new study was published this month in Nature Neuroscience and attempts to address this gap in our understanding. The study, conducted by postdoctoral fellow Dr. Jeffery Haines – whose fellowship is jointly funded by the MS Society and Fonds de Recherche du Québec – Santé (FRSQ) – and colleagues identified a molecular target that is thought to play a role in the axonal damage underlying MS and other neurodegenerative disorders. In addition, they tested a new class of compounds to see whether they could protect against this damage and halt the progression of disability.
Specifically, the group examined a protein called CRM1 (chromosome region maintenance protein 1), a molecular “shuttle” that transports important regulatory proteins out of the nucleus of nerve cells and into the surrounding gel-like compartment of the cell, called the cytoplasm. Previous research has shown that in certain neurodegenerative conditions, CRM1 is produced in abnormal quantities and forces these regulatory proteins to inappropriately accumulate in the cytoplasm, where they contribute to axonal damage. The aim of this study was to determine if inhibiting CRM1 could have a beneficial therapeutic role in preventing axonal damage and promoting neuroprotection.
The Study
The authors investigated two molecules that are known to inhibit CRM1 to determine if they could prevent axonal damage and halt progression of MS-like disease in mice. Firstly, however, they examined and compared CRM1 protein content in post-mortem brain tissue of people with MS versus healthy controls.
Subsequently, the authors induced an MS-like disease in mice and administered each of the CRM1 inhibitors or an inactive control drug after mice began to develop characteristic symptoms of MS. To determine whether the treatment can be used prophylactically to prevent disease onset and encourage neuroprotection, CRM1 inhibitors were also given before the MS-like disease was induced in a separate group of mice.
A wide variety of outcomes were measured to test the potential therapeutic benefits of the CRM1 inhibitors, including: progression of motor disability, axonal destruction in tissue samples, myelin repair, and inflammatory activity.
Finally, the authors set out to identify the specific molecular targets of the CRM1 inhibitors by screening molecules in the treated nerve cells that were retained in the cell nucleus, where they would have a neuroprotective effect.
Results
The authors found that CRM1 proteins levels were significantly higher in the brain tissue of people with MS compared to healthy controls, indicating that higher levels of this protein are associated with MS.
When they tested the CRM1 inhibitors in mice with an MS-like disease, they discovered that the inhibitors halted disease progression via a two-pronged approach that targets both neuroprotection and immune function. Specifically, while mice with MS-like disease developed paralysis of the hindlimbs, CRM1 inhibitors substantially improved motor function in these mice. Examination of nervous tissue showed that treatment with the inhibitors prevented further axonal destruction although, interestingly, this effect was not a result of stimulated repair of damaged myelin. Treating mice prophylactically was successful in reducing both disease onset and severity.
The authors also saw fewer inflammatory lesions and a reduction in the number of harmful immune cells following treatment with CRM1 inhibitors, both locally around lesions sites and in the peripheral bloodstream. They noted that the drug did not destroy or inactivate immune cells; rather, it worked by preventing them from rapidly multiplying.
Lastly, the authors found that when CRM1 was inhibited, certain proteins that have been associated with axonal damage in other disorders were retained in the nuclei of nerve cells, where they are thought to exert a neuroprotective effect.
Comment
Although therapies that target the immune system and modify the inflammatory process – termed immunomodulatory therapies – are the mainstay of treatments used to manage relapsing-remitting MS, they are nonetheless unable to stop the progression of axonal damage that leads to lasting disability. This study lays the foundation for a new approach to potentially combating progressive MS by exploring a new class of compounds that are both immunomodulatory and neuroprotective. An added benefit of these compounds is that they can be administered orally and easily cross the blood brain barrier to enter the central nervous system, making them promising candidates for drug testing and validation down the road. A great deal more work needs to be done, however, before these early but encouraging preclinical findings can be translated into viable treatment options for people living with MS.
Source
Haines JD et al. Nuclear export inhibitors avert progression in preclinical models of inflammatory demyelination. Nature Neurosci. 2015 Feb. [Epub Ahead of Print]