Nogo-A Antibodies for Progressive Multiple Sclerosis

Abstract

Solid pre-clinical data suggests Nogo-A-neutralization as a potential therapeutic approach for neuroinflammatory and demyelinating pathology. Nogo-A-antibodies are now in early clinical development for multiple sclerosis (MS). Their potential to boost axonal regeneration and compensatory fiber growth as well as myelin repair makes them an attractive candidate to treat also progressive MS in which neurodegeneration and chronic demyelination are hallmarks. AbstractMost of the current therapies as well as many of the clinical trials for Multiple Sclerosis (MS) target the inflammatory autoimmune processes, but less than 20% of all clinical trials investigate potential therapies for the chronic progressive disease stage of MS. The latter is responsible for the steadily increasing disability in many patients, and there is an urgent need for novel therapies that protect nervous system tissue and enhance axonal growth and/or remyelination. As outlined in this review, solid pre-clinical data suggest neutralization of the neurite outgrowth inhibitor Nogo-A as a potential new way to achieve both, axonal and myelin repair. Several phase I clinical studies with anti-Nogo-A antibodies have been conducted in different disease paradigms including MS and spinal cord injury. Data from spinal cord injury and amyotrophic lateral sclerosis (ALS) trials accredit a good safety profile of high doses of anti-Nogo-A-antibodies intravenously or intrathecally. An antibody against a Nogo receptor subunit, LINGO-1, was recently shown to improve outcome in acute optic neuritis in a phase II study. Nogo-A suppressing antibodies could be novel drug candidates for the relapsing as well as the progressive MS disease stage. In this review, we summarize the available pre-clinical and clinical evidence on Nogo-A and elucidate its potential use as a therapy for progressive MS.

What is the role of Brain derived neurotrophic factor in Multiple Sclerosis neuroinflammation?

“…Most available MS treatment have an exclusive anti-inflammatory effect helpful in reducing clinical and neuroradiological relapses but ineffective in preventing axonal loss and neurodegeneration. On the other hand, neuroprotective and/or remyelinating molecules failed to achieve the primary endpoint in clinical trials [76,77] . Conversely, brain delivery of BDNF has a potential role in reversing neurodegenerative diseases [78,79] but, so far, not through systemic administration.…”

Drug discovery for remyelination and treatment of MS

“…Interestingly, antibodies against Lingo‐1 are not the only ones shown to exhibit promising effects on myelin regeneration. Indeed, disruption to NogoR itself has also been shown to improve remyelination in a toxin‐based model of demyelination (Chong et al, ), and anti‐Nogo antibody‐based therapies have undergone phase I trials for prospective treatment of MS (Ineichen et al, ). The biology surrounding the Nogo–NogoR/Lingo1 is complex, (Schwab, ) as expression of Lingo1 in axons as well as oligodendrocytes can inhibit oligodendrocyte differentiation (Lee et al, ), highlighting possible bidirectional (axon‐oligodendrocyte) signaling between Nogo (or other ligands) and the NogoR–Lingo1‐p75 receptor complex.…”

Les anticorps monoclonaux en neurologie

“…La protéine Nogo-A, mais également son co-transporteur LINGO-1 (leucine-rich repeat and Ig domain-containing 1), font également l'objet de développements thérapeutiques dans la SEP. Le blocage de LINGO-1, qui est surexprimé à la surface des oligodendrocytes et des neurones dans la SEP, pourrait diminuer la destruction des gaines de myéline, préserver les axones, et aider à la remyélinisation [8][9]. expliquent cette primauté qui a permis des succès thérapeutiques majeurs.…”