Innovative Research Tool Pinpoints Potential Therapies for Multiple Sclerosis

Using a novel screening platform to rapidly evaluate the cellular effects of 1,000 chemical compounds, a team led by UC San Francisco scientists has identified eight drugs that may stimulate nervous system repair in multiple sclerosis (MS).

All eight compounds have previously been approved by the U.S. Food and Drug Administration (FDA) for the treatment of other conditions. One of the most promising agents is an antihistamine, though the scientists caution that MS patients should not use the drug until clinical trials have established whether it can safely and effectively treat MS, and if it does, what the proper dosages and treatment regimens would be. Because of the drugs emergence as a clear front-runner in the new study, a Phase 2 clinical trial to evaluate its effectiveness in MS is already underway at UCSF.

A major unmet need in the development of therapeutics for repair in MS has been the ability to screen compounds in a high-throughput manner, said Jonah Chan, PhD, the Debbie and Andy Rachleff Distinguished Professor of Neurology at UCSF and senior author of the new study. Through a great deal of serendipity, combined with the hard work of outstanding students and colleagues, we have been able to address this need, and I am happy that we are already testing one compound in the clinic.

The new research was published online July 6, 2014 in Nature Medicine.

The decision to focus on compounds already approved by the FDA was driven by study co-author Stephen L. Hauser, MD, the Robert A. Fishman Professor and chair of the Department of Neurology at UCSF. As founder and director of UCSFs interdisciplinary MS Research Group, Hauser has championed efforts to translate insights from basic neuroscience research into new therapies as quickly as possible. The new study is an exemplar of that strategy: only 14 months have elapsed since the team performed the first drug screen, and the Phase 2 trial is already at its halfway point.

Co-author Ari Green, MD, Debbie and Andy Rachleff Distinguished Professor of Neurology, is principal investigator on the Phase 2 trial at UCSF, which is known as the ReBUILD trial. According to Green, the trial was expedited by the FDAs granting of a New Drug Application exemption, which allows clinical researchers to study drugs in conditions for which they were not originally approved. The trial is still enrolling MS patients and is expected to be completed by the end of 2014.

In MS, the immune system goes awry and attacks myelin, a fatty sheath covering the thin nerve-cell extensions called axons that transmit signals in the brain. Much like the plastic covering on electrical wiring, myelin provides insulation that is crucial to quick, efficient communication among neurons. Poor neural conduction leads to the range of progressively worsening symptoms of MS. Myelin degeneration damages axons and ultimately causes nerve cells to die off.

Myelin is formed by specialized cells called oligodendrocytes, which wrap themselves around axons in multiple layers. This wrapping process, known as myelination, has generally been studied in combined cultures of neurons and oligodendrocytes, and until recently it was widely believed that axons provide some chemical signal to oligodendrocytes that initiates myelination.

But in 2012, Chan and colleagues published studies showing that oligodendrocytes will myelinate synthetic nanofibers of approximately the same diameter as axons. Though this work showed that it was possible to study myelination in oligodendrocytes alone, the configuration of the fibers used in the experiments made it difficult to automate the detection and quantification of myelination, which are essential criteria to efficiently screen drugs that might stimulate remyelination to treat MS.

To address these problems, Chans research group designed a new system based around precisely fabricated conical micropillars. Each micropillar is only a few thousandths of an inch thick at its base, and 10,000 of them can fit within a 5-millimeter-square well. Chans team created plates of 96 micropillar wells and loaded up each well with 40,000 oligodendrocyte precursor cells (OPCs), the cells from which oligodendrocytes are derived in the brain and spinal cord.

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Innovative Research Tool Pinpoints Potential Therapies for Multiple Sclerosis