Research led by UCSF has pointed to a hallmark of disease repair that could be used in the development of future treatments.
Ten years after the discovery of a common antihistamine, clemastine, as a potential treatment for multiple sclerosis by researchers at UC San Francisco, a new method has been developed to evaluate the drug’s effectiveness in repairing the brain. This development could also facilitate the assessment of potential future treatments for the devastating disorder.
Led by physician-scientist Ari Green, MD, who, along with neuroscientist Jonah Chan, Ph.D., originally pinpointed clemastine’s potential therapeutic role for MS, MRI scans were used to examine the drug’s effects on the brains of 50 clinical trial participants .
In MS, patients lose myelin, the protective insulation around nerve fibers. This myelin loss triggers delays in nerve signals, leading to weakness and spasticity, vision loss, cognitive slowing, and other symptoms.
In the brain, water trapped between the thin layers of myelin that surround nerve fibers cannot move as freely as water that flows between brain cells. This unique property of myelin allowed imaging experts to develop a technique to compare the difference in myelin levels before and after the drug was administered, by measuring the so-called myelin water fraction, or the ratio of myelin water to the total water content of the brain tissue.
In their study, published May 8, 2023 in PNAS, the researchers found that patients with MS who were treated with clemastine experienced modest increases in myelin water, indicating myelin repair. They also proved that the myelin water fraction technique, when focused on the right parts of the brain, could be used to track myelin recovery.
“This is the first example of brain repair being documented on MRI for a chronic neurological condition,” said Green, medical director of the UCSF Multiple Sclerosis and Neuroinflammation Center and member of the Weill Institute for Neurosciences. “The study provides the first direct, biologically validated, imaging-based evidence of myelin repair induced by clemastine. This will set the standard for future research into remyelinating therapies.”
Myelin increased even after medication was stopped
In the study, patients with MS who participated in the ReBUILD study were divided into two groups: the first group received clemastine for the first three months of the study, and the second group only received clemastine for months three to five. Using the myelin water fraction as a biomarker, the researchers found that myelin water increased in the first group after participants received the drug, and continued to increase after clemastine was stopped. In the second group, the myelin water fraction showed a decrease in myelin water in the first part of the study, under placebo, and a rebound after the participants received clemastine.
The findings confirm the findings of a previous study with the same 50 patients, which had found that the allergy medication reduced delayed nerve signaling, potentially relieving symptoms.
In the current study, researchers looked at the corpus callosum, a region of the brain with a high myelin content that connects the right and left hemispheres of the brain. They found that significant repair occurred outside the visible lesions typically associated with MS. This emphasizes the need to focus on myelin repair beyond these lesion sites.
Clemastine works in this setting by stimulating the differentiation of myelin-forming stem cells. This places the drug a generation ahead of existing MS drugs that work by suppressing immune system activity, reducing inflammation and reducing the risk of relapse. However, it is still not ideal, making measurement of the water fraction an important tool for developing better therapy.
“Clemastine may only be partially effective at the doses we can use,” said Green, who is also a neuro-ophthalmologist and chief of the Division of Neuroimmunology and Glial Biology in the UCSF Department of Neurology. “It can be sedating, which can be particularly undesirable in patients with MS. We hope that better drugs will be developed, but clemastine has proven to be the tool to show that remyelination is possible.”
Proposed future research will examine clemastine’s potential for treating brain damage in premature infants, who often experience myelin damage. Pediatric neurologist Bridget Ostrem, MD, Ph.D., of UCSF Benioff Children’s Hospitals, is currently seeking approval from the Food and Drug Administration to begin the first clinical trial testing clemastine for the treatment of this debilitating and debilitating condition.
Reference: “MWF of the corpus callosum is a robust measure of remyelination: Results from the ReBUILD trial” by Eduardo Caverzasi, Nico Papinutto, Christian Cordano, Gina Kirkish, Tristan J. Gundel, Alyssa Zhu, Amit Vijay Akula, W. John Boscardin, Heiko Neeb, Roland G. Henry, Jonah R. Chan, and Ari J. Green, 08 May 2023, Proceedings of the National Academy of Sciences.
The study was supported by The Rachleff Family Westridge Foundation, the Janet Lustgarten and Lustgarten Family Whitney Fund, and the Adelson Medical Research Foundation.