The complexity in underlying mechanisms, a lack of representative research models, and inconsistent criteria defining therapeutic benefit are the main reasons why an effective therapy for progressive forms of multiple sclerosis (MS) is still lacking, researchers maintain in a review study.
Nevertheless, as research continues to shed light on the root causes of the disease, scientists will move closer to finding targeted, effective treatments, the authors say.
The article, “Progressive multiple sclerosis: from pathophysiology to therapeutic strategies,” was published in the journal Nature Reviews Drug Discovery.
Although progress has been made in developing new therapies for relapsing-remitting MS (RRMS), treatment of progressive forms of MS — characterized by gradual accumulation of disability — without acute flares (relapses) or remissions, remains unsatisfactory.
Some patients experience progressive disease from the beginning of symptoms, referred to as primary progressive MS (PPMS), while others experience it as a later stage following RRMS, in which case it is called secondary progressive MS (SPMS).
In the review study, an international team of researchers, including doctors at St. Josef-Hospital, University Hospital at Ruhr-Universität Bochum (RUB), in Germany, and collaborators at the University of Calgary and the University of Alberta, Canada, joined to discuss how much is known about the mechanisms underlying progressive MS, and the potential treatments being explored. The setbacks encountered and future challenges also were discussed.
Emerging therapies in MS currently include those targeting inflammation and nerve cell death (neurodegeneration), as well as those promoting remyelination — that is, the repair of myelin, which is the fatty coating that surrounds and insulates nerve cells, and is destroyed in MS.
“A bottom line of our analysis is that the reason why it is so difficult to treat progressive MS is the fact that progression is caused by various mechanisms,” Simon Faissner, MD, said in a RUB press release written by Julia Weiler. Faissner is a professor at RUB and the study’s lead author.
According to the team, finding therapies for progressive MS remains an unmet need due to the complexity of mechanisms involved. Several disturbances converge: chronic inflammation with activation of microglia (specialized immune cells of the brain and spinal cord), and involvement of immune T-cells and B-cells; in turn, inflammation can lead to an energy deficit in nerve cells, harming their functioning; plus, the environment associated with MS lesions inhibits cell growth and also impairs remyelination.
Moreover, nerve fibers devoid of myelin also change their set of ion channels, accelerating the neurodegeneration process.
“In order to provide more efficient treatment, we will probably need precise therapy approaches targeting various pathomechanisms [disease mechanisms],” Faissner said.
Another problem is that the animal models currently available for researchers to study the disease and test potential treatments cannot mimic the full range of mechanisms underlying progressive MS.
That is why identifying potential therapeutic agents for a clinical study, for instance, “poses a considerable challenge,” said Faissner.
Another reason why it has been difficult to find treatments for progressive MS is the inconsistent efficacy criteria often used in clinical studies, the team said. Frequently, studies rely on different objectives, which means the way therapeutic success is understood and assessed varies from study to study.
Ideally, uniform criteria should be implemented to make studies comparable, and provide trustful results.
There also are financial aspects impeding the development of new therapies. According to Faissner, medications approved for other conditions could prove effective against progressive MS, but because patents for such products have expired, “pharmaceutical companies can’t further develop them.”
“The implementation of studies to test the efficacy of those drugs for MS often fails due to a lack of funds,” Faissner said.
Despite the challenges, researchers believe treatment for people with progressive MS will improve, as scientists gain a deeper understanding of the underlying disease mechanisms.
In Faissner’s opinion, these findings “will enable us to introduce a more targeted therapy that will prevent patients from suffering more severe impairments as the disease progresses.”
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