Although multiple sclerosis (MS) is dominated by a progressive phase of the disease, few therapies are available to modify clinically defined progression. There is a significant unmet need for treatments targeting the delayed neurodegenerative components of the disease, said Gavin Giovannoni, MBBCh, PhD, Chair of Neurology, Blizard Institute of Cell and Molecular Science, Queen Mary University of London, England, at the 2016 American Academy of Neurology annual meeting.
“We need a multilayered approach to target the pathogenic processes that underpin progressive MS. This includes antiinflammatory therapies targeting both adaptive and innate immune mechanisms, neuroprotective therapies, and remyelination strategies,” noted Dr Giovannoni.
“The aim of neuroreparation is to restore lost function. Enhancing mechanisms related to axonal and synaptic plasticity with pharmacologic interventions remains an area of active research,” he added.
Based on the current understanding of MS, neuroprotective strategies are needed for acute MS with actively inflamed lesions, and for chronic MS to target delayed, secondary neurodegeneration.
“Neuroprotection is indicated in all stages of the disease to try to delay and prevent neuroaxonal loss to maintain reserve capacity,” Dr Giovannoni explained.
Several neuroprotective therapies are being investigated for MS, including:
- Sodium channel blockers (phenytoin, lamotrigine, riluzole, oxcarbazepine)
- Acid-sensing ion channel 1 blockers (amiloride)
- Selective serotonin reuptake inhibitors (fluoxetine)
- Phosphodiesterase inhibitors (ibudilast)
- Microglial inhibitors (laquinimod, minocycline)
- Drugs targeting mitochondrial function (biotin, idebenone, MitoQ).
There is no point in using neuroprotection strategies unless they are used in combination with an anti-inflammatory regimen to “switch off autoimmune-driven focal inflammation that is the main driver of both acute and chronic neuroaxonal loss,” said Dr Giovannoni.
Similarly, remyelination strategies will only work if there is preservation of axons that target remyelination, he added.
“What is the point of promoting remyelination if the initial autoimmune-driven inflammatory events are not suppressed? The newly formed myelin may simply become a target for further rounds of inflammatory attack,” he emphasized.
Several potential remyelination therapies are in preclinical and/or early clinical development. Meanwhile, magnetic resonance imaging and positron emission tomography imaging are being used to assess whether remyelination strategies are feasible in vivo, said Dr Giovannoni.
The most advanced remyelination therapy targets LINGO-1, a protein that interacts with the Nogo receptor to inhibit myelination.
“Across several animal models, LINGO-1 inhibition has been shown to promote neuron and oligodendrocyte survival, axon regeneration, oligodendrocyte differentiation, remyelination and functional recovery. The inhibition of LINGO-1 therefore presents a novel therapeutic approach for the treatment of MS,” said Dr Giovannoni.
In a randomized, double-blind, placebo-controlled clinical trial known as RENEW, patients with a first episode of unilateral acute optic neuritis who received anti–LINGO-1 showed improved optic nerve conduction latency at week 24 in the per-protocol analysis. “This is consistent with remyelination following a first episode of acute optic neuritis,” said Dr Giovannoni.
In addition to anti–LINGO-1, the following remyelination therapies are being assessed in preclinical and/or clinical trials:
- Retinoid X receptor agonists (IRX4204)
- Muscarinic antagonists (benztropine)
- Antihistamine H3 antagonists (GSK-239512, clemastine)
- Anti-SEMA4D (VX15)
Alternative HypothesisAlthough the working hypothesis is that MS is an autoimmune disease, skeptics in the field remain open to the possibility that MS may be caused by a virus.
“The viral hypothesis is that damage of the oligodendrocytes, due to direct viral infection, secondarily triggers a focal inflammatory reaction. One way of proving, or disproving, this hypothesis is through well-designed clinical trials,” said Dr Giovannoni.