Detecting Nervous System Repair in MS: International Workshop Findings Published
What if a new therapy was developed to protect brain cells from damage and even regenerate new cells to repair damage caused by MS, but there was no way to prove that it works? The question of how to detect nervous system protection and repair in people with MS – without having to wait possibly years to observe a person’s disease progression – was the theme of a workshop recently convened in Amsterdam by the National MS Society’s International Advisory Committee on Clinical Trials. The workshop, co-chaired by Frederik Barkhof, MD, PhD (VU Medical Centre, Amsterdam) and Peter Calabresi, MD (Johns Hopkins University, Baltimore), included nearly 60 participants from North America and Europe who grappled with key questions about applying emerging technologies to clinical trials of repair and protection therapies. The workshop discussions and background literature formed the basis of a new paper published in the May 2009 issue of Nature Reviews Neurology 5, 256-266 – free access to all readers).
Background: The focus of the “Imaging Outcomes for Protection and Repair in MS” workshop stemmed from the Stem Cell Research Summit (PDF format), held jointly by the Society and the MS International Federation in 2007. Discussions there of potential cell therapies made it obvious that we needed better non-clinical tools to reliably and sensitively determine in early stages of clinical testing whether new therapies could protect and even repair the nervous system. Imaging techniques (such as MRI, magnetic resonance imaging) were deemed to be the most promising to provide such “proof-of-concept” information, and thus became the focus of the Amsterdam workshop.
The Paper: The authors rated available imaging techniques on several criteria to determine the most promising options for use in nerve repair and protection studies, such as whether the technologies could differentiate between different types of tissue damage; how sensitive they would be in picking up improvements or worsening of disease activity; and whether results correlated with clinical symptoms. Three specific imaging technologies stood out:
OCT (optical coherence tomography) is a relatively easy tool that uses infrared light to measure the thickness of the nerve fiber layer of the retina, in the back of the eye, which contains nerve fibers that make up the optic nerves. Studies are beginning to suggest a role for OCT in assessing nerve fiber damage in MS, and also in evaluating the success of therapies that may protect nerve tissues or grow new tissue. “OCT seems to be a promising tool for quantifying nerve injury after acute optic neuritis,” wrote Dr. Barkhof and colleagues. “And the currently available data suggest that this measure could be used as a primary outcome in a phase II study that examines preliminary efficacy of a neuroprotective agent.”
MTR (magnetic transfer ratio) is an experimental technology that involves delivering energy to protons in the brain and then measuring how much is transferred or absorbed. Lower levels of energy absorption at a particular MS lesion are thought to indicate degrees of tissue damage. The authors conclude that this method, along with MRI-detected “black holes” (indicating areas of permanent damage), provide an opportunity to monitor the evolution of tissue damage and neuroprotection and repair over the course of 6–9 months.
Whole-brain volume measurement: The brains of people with MS tend to atrophy, or shrink, over time, and imaging techniques that measure brain atrophy are well studied. The authors note that these measurements have excellent sensitivity to changes in disease course (because decreases in brain volume seem to correlate with increased disability), but do not distinguish well between types of tissue damage. They conclude that brain volume change detected with serial MRIs can provide a sensitive overall measure of neuroprotection in MS trials over the course of one year.
The authors conclude that the “best strategy” for clinical trials is to use a combination of these outcome measures to determine the neuroprotective capacity of an experimental agent. Although more data is needed that directly compare these measures in people with the disease, they comment that “measurement of neuroprotection by imaging is feasible in MS.”
Comment: “We’re at a turning point in MS, and clinical trials are on the horizon to test new strategies for repairing or protecting the nervous system in people with MS,” said John Richert, MD, Executive Vice President of Research & Clinical Programs at the Society. “This review, by an international panel of experts, is a major step toward finding accurate ways to measure whether repair or protection strategies are working. These methods have the potential to distinguish between repair of nerve fibers and the myelin that ensheathes them, and some can provide crucial information within a fraction of the time that would be needed if we had to rely solely on observing clinical signs of people’s MS progression.”