BARCELONA—Researchers are actively seeking means of promoting myelin repair in patients with multiple sclerosis (MS), and some drugs have advanced from the preclinical to the clinical phase, according to an overview presented at the 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). The therapy furthest along in development is the anti-LINGO1 monoclonal antibody, which promotes endogenous remyelination. Exogenous strategies for myelin repair are still in preclinical stages, and perhaps the most promising of these methods relies on induced pluripotent stem cells.
“There is still a crucial need of markers: clinical markers of repair, biomarkers of repair, [and] imaging markers of repair,” said Catherine Lubetzki, MD, PhD, Professor of Neurology at Pierre and Marie Curie University in Paris. Trial designs for remyelinating strategies also need to be optimized, she added.
Exogenous Strategies
Exogenous strategies introduce myelinating cells into the patient. Oligodendrocyte progenitor cells (OPCs), Schwann cells, and neuronal stem cells are under investigation as potential exogenous methods of remyelination.
Induced pluripotent stem cells have been the major advance in this area in the past several years, said Dr. Lubetzki. Investigators use a mixture of transcription factors to induce skin fibroblasts to become stem cells, and then reprogram them into an oligodendrocyte cell phase. This method can enable autologous grafts. Goldman and colleagues transplanted OPCs generated from human fibroblasts into the brains of dysmyelinating mutant mice. The OPCs promoted extensive remyelination and improved the mice’s survival.
Selecting Candidates Based on Their Mechanisms
One method of selecting drug candidates that could promote endogenous remyelination is based on the molecules’ mechanisms of action. Dr. Lubetzki and colleagues studied eliprodil because of its known neuroprotective properties. In 1999, they demonstrated that eliprodil strongly stimulated CNS myelination in an in vitro system of myelination.
More recently, Dr. Lubetzki and colleagues have been investigating molecules that guide OPCs to demyelinated areas. In a proof-of-concept study, the investigators found that semaphorin 3F performs such a function. They also concluded that speeding the recruitment of OPCs to demyelinated plaques results in accelerated remyelination. Approximately one year ago, the team began an ongoing preclinical study in which they are overexpressing semaphorin 3F at lesion sites to speed the recruitment of OPCs and accelerate the remyelination process. The goal is to stimulate remyelination during the window of time when axonal damage is reversible, said Dr. Lubetzki.
Perhaps the best-known investigational strategy for promoting endogenous repair involves the protein LINGO1. Researchers at Biogen found that when LINGO1 is expressed at the surface of immature oligodendrocytes, the protein blocks their maturation and prevents myelination. They developed a monoclonal antibody to suppress the expression of LINGO1, thus allowing oligodendrocytes’ maturation to proceed and improving myelination and remyelination.
The anti-LINGO1 monoclonal antibody yielded positive results in experimental models, and investigators subsequently began two phase II studies of the treatment in humans. Results of the first study were reported at ECTRIMS; the monoclonal antibody improved full-field visual evoked potential latency in patients with acute optic neuritis, and this result was consistent with improved remyelination. The other phase II study includes 419 patients with relapsing-remitting MS and is ongoing.
Screening Banks of Molecules
The other main approach to selecting drug candidates that could promote endogenous remyelination is to screen a large bank of molecules. This approach “will lead to an increasing number of candidates and new screening tools,” said Dr. Lubetzki.
Several years ago, Tesar and colleagues developed a method of deriving OPCs from epiblast stem cells. The investigators recently used this cellular model to perform high-throughput screening of a large library of bioactive small molecules. They identified seven compounds that, at low concentrations, enhanced the generation of mature oligodendrocytes from OPCs. After they validated this method in various models, Tesar and colleagues identified two drug candidates: miconazole, an antifungal drug, and clobetasol, an immunosuppressant. The researchers now have “a strong rationale for translation into human subjects with MS,” said Dr. Lubetzki.
In 2014, Chan et al developed a micropillar array system for screening molecules. Oligodendrocytes placed in the array are able to wrap membrane around the micropillars, and investigators can measure the thickness of the membrane. The method thus is a binary indicant of the presence or absence of myelination. When Chan and colleagues used the micropillar array model to perform high-throughput screening, they identified a cluster of antimuscarinic compounds that enhanced oligodendrocyte differentiation. One of these drugs was clemastine, an antihistaminic compound that promotes myelination. Researchers are studying clemastine as a remyelinating agent in an ongoing phase II study of 50 patients with relapsing-remitting MS.