Intrathecal Rituximab Therapy in Multiple Sclerosis: Review of Evidence Supporting the Need for Future Trials

Bonnan, Mickaël; Ferrari, S.; Bertandeau, E.; Demasles, Stéphanie; Krim, E.; Miquel, Marie; Barroso, Bruno

doi:10.2174/1389450115666141029234644

Cited by 21 publications

(17 citation statements)

References 103 publications

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“…Third, given the presumable intrathecal compartmentalization of inflammation in the progressive stage, a potential drug needs to reach the CNS tissue in spite of a mostly intact BBB [25,106], e.g. by intrathecal application [107], or delivery into the CSF space via a shuttle system. Intrathecal application leads to locally maximized drug concentrations with low systemic exposure and can therefore be expected to have minimal systemic side effects [107].…”

Section: Requirements For Novel Ms Therapiesmentioning

confidence: 99%

“…by intrathecal application [107], or delivery into the CSF space via a shuttle system. Intrathecal application leads to locally maximized drug concentrations with low systemic exposure and can therefore be expected to have minimal systemic side effects [107]. Fourth, besides immunomodulation and neuro-/myelin protection, the regenerative effects of treatments like anti-Nogo-A should foster repair as much as possible in this phase of disease.…”

Section: Requirements For Novel Ms Therapiesmentioning

confidence: 99%

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

et al. 2017

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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...

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Section: Requirements For Novel Ms Therapiesmentioning

confidence: 99%

Section: Requirements For Novel Ms Therapiesmentioning

confidence: 99%

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

et al. 2017

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“…Interestingly, GM haplotypes are in almost total linkage disequilibrium among world populations and are therefore typical of geographic origin unless there is a genetic admixture [60]. Gm21* haplotypes were associated with high ITS in a Caucasian population although Gm5*;3 haplotypes are associated with a low level of ITS 96,97 . Studies are required concerning non-Caucasian (African and Asian descent) haplotypes.…”

Section: Factors Influencing Its Levelmentioning

confidence: 99%

“…Given the low diffusion of rituximab to CSF (<0.2%) and the growing body of evidence demonstrating the safe use of intrathecally infused rituximab, a rationale to infuse intrathecal rituximab in progressive MS recently emerged (review in reference [96]). Data obtained from a single patient receiving intrathecal rituximab (10 mg per month for 2 months) showed a major effect upon CSF cytokine levels although intrathecal IgG synthesis was unchanged [97,98] (unpublished).…”

Section: None Of the Available Ms Drugs Deplete Intrathecal Ig Synthesismentioning

confidence: 99%

Intrathecal Immunoglobulin Synthesis in MS—A Complete Reappraisal

Bonnan¹

2016

Trending Topics in Multiple Sclerosis

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Multiple sclerosis (MS) is characterized by the intrathecal synthesis (ITS) of immunoglobulins (Igs), which, although nonspecific, is the strongest biological marker. Since no specific target has been elucidated, this synthesis is considered to be disease-irrelevant. We demonstrate that this synthesis provides pertinent information about the pathophysiological processes involved. Quantification of ITS is based on an approximation intrinsically underestimating its level and it remains constant in MS, albeit sometimes at a low level. B-cell maturation seems to be initiated within the cervical lymph nodes and B-cells traffic on both sides of the blood-brain barrier by rounds of bidirectional traffic. During this process, they undergo somatic hypermutation, which is the hallmark of antigen-driven antibody maturation, suggesting that most of the ITS is probably directed against as yet unknown targets. Alternatively, examining"non-disease-relevant" ITS in the light of meningeal tertiary lymphoid organs provides new insights into the pathophysiology of MS. Although no specific target has yet been identified in MS, recent developments in the search for targeted antigens point to non-conventional antigens (posttranslationally modified proteins or oxidized products) of which a few are promising for future research.

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“…The results from preplanned subgroup analyses, however, suggested that it may affect disease progression in younger patients, particularly those with inflammatory lesions on brain MRI [14]. Given that the progressive phase of MS is thought to be associated with intrathecal compartmentalization of inflammatory cells, it has been suggested that intrathecal administration of immunosuppressants may represent a promising new approach in progressive MS [114]. A phase II trial of combined IV and intrathecally administered rituximab (vs placebo) in patients with SPMS is currently ongoing (NCT01212094).…”

Section: Rituximab and Ocrelizumab: 2 Anti-cd20 Monoclonal Antibodiesmentioning

confidence: 99%

Therapeutic Advances and Future Prospects in Progressive Forms of Multiple Sclerosis

2016

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Identifying effective therapies for the treatment of progressive forms of multiple sclerosis (MS) is a highly relevant priority and one of the greatest challenges for the global MS community. Better understanding of the mechanisms involved in progression of the disease, novel trial designs, drug repurposing strategies, and new models of collaboration may assist in identifying effective therapies. In this review, we discuss various therapies under study in phase II or III trials, including antioxidants (idebenone); tyrosine kinase inhibitors ( m a s i t i n i b ) ; s p h i n g o s i n e r e c e p t o r m o d u l a t o r s (siponimod); monoclonal antibodies (anti-leucine-rich repeat and immunoglobulin-like domain containing neurite outgrowth inhibitor receptor-interacting protein-1, natalizumab, ocrelizumab, intrathecal rituximab); hematopoetic stem cell therapy; statins and other possible neuroprotective agents (amiloride, riluzole, fluoxetine, oxcarbazepine); lithium; phosphodiesterase inhibitors (ibudilast); hormone-based therapies (adrenocorticotrophic hormone and erythropoietin); T-cell receptor peptide vaccine (NeuroVax); autologous T-cell immunotherapy (Tcelna); MIS416 (a microparticulate immune response modifier); dopamine antagonists (domperidone); and nutritional supplements, including lipoic acid, biotin, and sunphenon epigallocatechin-3-gallate (green tea extract). Given ongoing and planned clinical trial initiatives, and the largest ever focus of the global research community on progressive MS, future prospects for developing targeted therapeutics aimed at reducing disability in progressive forms of MS appear promising.

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Intrathecal Rituximab Therapy in Multiple Sclerosis: Review of Evidence Supporting the Need for Future Trials

Cited by 21 publications

References 103 publications

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

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

Intrathecal Immunoglobulin Synthesis in MS—A Complete Reappraisal

Therapeutic Advances and Future Prospects in Progressive Forms of Multiple Sclerosis

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