Nogo-A antibodies enhance axonal repair and remyelination in neuro-inflammatory and demyelinating pathology

Abstract

Two hallmarks of chronic multiple sclerosis lesions are the absence of significant spontaneous remyelination and primary as well as secondary neurodegeneration. Both characteristics may be influenced by the presence of inhibitory factors preventing myelin and neuronal repair. We investigated the potential of antibodies against Nogo-A, a well-known inhibitory protein for neuronal growth and plasticity, to enhance neuronal regeneration and remyelination in two animal models of multiple sclerosis. We induced a targeted experimental autoimmune encephalomyelitis (EAE) lesion in the dorsal funiculus of the cervical spinal cord of adult rats resulting in a large drop of skilled forelimb motor functions. We subsequently observed improved recovery of forelimb function after anti-Nogo-A treatment. Anterograde tracing of the corticospinal tract revealed enhanced axonal sprouting and arborisation within the spinal cord gray matter preferentially targeting pre-motor and motor spinal cord laminae on lesion level and above in the anti-Nogo-A-treated animals. An important additional effect of Nogo-A-neutralization was enhanced remyelination observed after lysolecithin-induced demyelination of spinal tracts. Whereas remyelinated fiber numbers in the lesion site were increased several fold, no effect of Nogo-A-inhibition was observed on oligodendrocyte precursor proliferation, migration, or differentiation. Enhancing remyelination and promoting axonal regeneration and plasticity represent important unmet medical needs in multiple sclerosis. Anti-Nogo-A antibodies hold promise as a potential new therapy for multiple sclerosis, in particular during the chronic phase of the disease when neurodegeneration and remyelination failure determine disability evolution. Key pointsSolid 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 injur...

Antibody signatures in patients with histopathologically defined multiple sclerosis patterns

“…Studying spinal cord injury and stroke in animal models, it was shown that the neutralization of Nogo-A with antibodies facilitates axonal growth and functional recovery [8,81]. Using the MS mouse model EAE, blocking Nogo-A receptors ameliorated the disease course, boosted functional recovery, and increased axonal sprouting and remyelination [28,30]. Antibodies are thought to neutralize inhibitory effects of Nogo-A and thus to activate axonal and myelin regeneration.…”

Axonal mitochondria across species adjust in diameter depending on thickness of surrounding myelin

“…We thus assessed whether myelin-axons were able to maintain the positive correlation between axonal mitochondria diameter and G-ratio during de-and remyelination. The two commonly used experimental models to study demyelination and subsequent remyelination uses; cuprizone, a dietary copper-chelating agent, and lysolecithin (LPC), an intraparenchymally injected detergent [3,14,30].…”

Microenvironment Imbalance of Spinal Cord Injury

“…Although spared and regenerated axons are myelinated, the conductive function of the axons does not change 49 . Thus, many studies demonstrated SCI repair and recovered spinal cord function through the restoration of the myelin sheath 50 – 52 . Our team transplanted autologous activated Schwann cells into the spinal cord, and we found relatively complete restoration of the myelin sheath and improved microenvironment balance 53 , and another study demonstrated similar results when co-transplanting human umbilical cord mesenchymal stem cells and human Schwann cells 54 .…”