Turning cyclotide against MS: MRI pointer

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  • Published: Apr 1, 2016
  • Author: David Bradley
  • Channels: MRI Spectroscopy
thumbnail image: Turning cyclotide against MS: MRI pointer

MS and MRI

An animal model of multiple sclerosis shows that early detection with magnetic resonance imaging (MRI) followed by immediate treatment with a synthetic plant peptide known as a cyclotide could prevent the development of the symptoms to full-blown MS. (Credit: PNAS. Gruber et al)

An animal model of multiple sclerosis shows that treatment with a synthetic plant peptide known as a cyclotide, a circular peptide, could prevent the development of multiple sclerosis (MS) symptoms.

Scientists at MedUni Vienna, the Medical University of Vienna, in Austria, have taken an important step in treating the debilitating and currently incurable disease, MS. Christian Gruber and colleagues in Australia, Germany and Sweden have demonstrated how treatment with a novel, orally active cyclic peptide as soon as the first signs of the disease are detected by magnetic resonance imaging (MRI) could preclude full onset.

"The one-off oral administration of the active agent brought about a great improvement in symptoms," explains Gruber, Chief Researcher at the Center for Physiology and Pharmacology. "There were no further attacks of the disease. This could slow down the course of the disease in general."

Modulating autoimmunity

MS is a chronic inflammatory autoimmune disease of the central nervous system. It arises when auto-reactive T cells induce destruction of the myelin sheath around nerve fibres, demyelination and subsequent neuronal degradation. Communication within the nervous system degrades leading to a range of physical and mental symptoms including double vision or blindness in one eye, muscle weakness, loss of tactile sensation and trouble with the coordination of movement. The disease progresses in the form of attacks or episodes and although there are several approaches that help patients cope, to some degree, with the symptoms it is incurable, and available drugs have to be administered intravenously as well as having severe side effects.

An MS episode is defined by the occurrence of new symptoms or flare-ups of pre-existing ones. Each episode is associated with immediate or deferred deterioration in the patient's condition. Unfortunately, the underlying cause of the inflammation within the nervous system is only partially understood. Researchers estimate that there are approximately 2.5 million people around the world suffering from MS.

The new study highlights the potential for cyclotides as orally active immunosuppressive in the treatment of MS model experimental autoimmune encephalomyelitis, without inducing major adverse effects. Cyclotides are macrocyclic plant peptides that are present in most common plant families, including coffee, violet, squash, grasses and plants of the nightshade family. They represent a large and diverse group of natural products.

Clinical trials

The discovery made by the Austrian scientists now offers hope that the disease can be halted at a very early stage or, at the very least, its progression greatly retarded. "As soon as functional neurological problems occur and an MRI scan identifies early pathological changes in the central nervous system, the drug could be given as a basic therapy, the team explains. In their animal model of MS, symptoms were reduced markedly by oral administration of a cyclotide drug. Gruber and Schabbauer suggest that it might be possible to extend considerably the interval between episodes (attacks) or possibly prevent an onset of the disease using a cyclotide.

The mode of action of cyclotides has been known for three years ago, having been identified by the scientists in Vienna working with their colleagues at Freiburg University Hospital. The compounds fundamentally inhibit the messenger substance interleukin-2 and so halt the division of T cells that would otherwise be triggered by its message. Thus blocked, these "killer" cells of the immune system are no longer able to wreak havoc on the nervous system. The same mode of action might also be exploited by using a cyclotide to inhibit the autoimmune response in other disorders, such as rheumatoid arthritis.

The team explains in the journal, Proceedings of the National Academy of Sciences, that the work provides a proof of principle that cyclic peptides derived from plants can serve as oral active therapeutics, utilizing their intrinsic bioactivity and stable three-dimensional structure. Taken as a whole, cyclotides are considered to be a combinatorial peptide library and so there are myriad forms they can take any one of which might be used for a specific application in modulating autoimmune disease.

On the basis of this development, MedUni Vienna and Freiburg University Medical Center have filed patent applications in several countries and licensed the discovery to Cyxone, a company established to carry out further research and development. The aim of this collaboration is to develop a safe, orally active drug for treating MS. A Phase I clinical trial for this could start in 2018, suggests Gruber.

Related Links

Proc Natl Acad Sci 2016, online: "Oral activity of a nature-derived cyclic peptide for the treatment of multiple sclerosis"

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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