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Remyelination therapy goes to trial for multiple sclerosis.

Brugarolas P, Popko B - Neurol Neuroimmunol Neuroinflamm (2014)

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, The University of Chicago, Chicago, IL.

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A current thought in the MS therapeutics community is that drugs that enhance remyelination may be more effective in reducing long-term disability... This hypothesis is based on the observation that disability in MS increases with age as the capacity of oligodendrocytes to remyelinate decreases... Additional support for this hypothesis comes from extensive preclinical studies showing that promoting remyelination either by transplanting myelinating stem cells or by pharmacologic enhancement of endogenous myelination processes reduces clinical severity in animal models of MS... BIIB033 is thought to disrupt some or all of these interactions, leading to the activation of pathways critical for myelination (figure)... Most monoclonal antibodies, and BIIB033 is no exception, have low penetration into the CNS, which suggests that very high doses may be required to obtain a therapeutic effect... The researchers measured the concentration of BIIB033 in CSF and concluded that doses higher than 10 mg/kg may result in concentrations in the CNS equivalent to those shown to enhance remyelination in animal models of MS... One of the drawbacks of antibody therapies is that patients may develop an immune response against the therapeutic molecule, rendering the drug no longer useful in those patients... In this article, they evaluated the rate of production of antibodies against BIIB033 and found it to be low... While this is encouraging, in this study the patients received only 1 or 2 doses of the drug, which is not representative of the therapeutic paradigm in the long-term... Unfortunately, they also found antibodies against BIIB033 in one placebo-treated individual (false-positive), which indicates that a better assay may be needed... The phase II trial for BIIB033 will be carried out in combination with Avonex (interferon beta), which is one of the front-line anti-inflammatory MS drugs currently in use... Over the past decade considerable effort has been exerted to develop therapeutic strategies to enhance myelin repair... These attempts have been based largely on a significant body of data that has defined the intrinsic and extrinsic factors that drive oligodendrocyte maturation and the myelination process... The anti-LINGO-1 trial is likely the first of many that will test drugs that have been shown to enhance remyelination in murine models... Soon we should know whether this approach will provide benefit to patients with MS, which would be the first evidence that enhancing myelin repair may alter the course of this disease.

No MeSH data available.


Possible signaling pathways that anti-LINGO-1 antibody may modulateCellular specificity of these interactions remains to be fully elucidated.
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Figure 1: Possible signaling pathways that anti-LINGO-1 antibody may modulateCellular specificity of these interactions remains to be fully elucidated.

Mentions: BIIB033 targets LINGO-1, a protein expressed in oligodendrocytes and neurons that has been shown to naturally inhibit oligodendrocyte differentiation and myelination.7 This protein was also found to have increased expression in oligodendrocyte precursors from MS lesions.8 These discoveries led to the hypothesis that LINGO-1 inhibitors may enhance remyelination, which was later demonstrated using an anti-LINGO-1 antibody in several animal models of demyelination.9 LINGO-1 is a leucine-rich repeat and immunoglobulin domain-containing Nogo receptor-interacting protein shown to interact with EGFR, ErB2, NgR1, and TrkB receptors in the CNS.8 BIIB033 is thought to disrupt some or all of these interactions, leading to the activation of pathways critical for myelination (figure).


Remyelination therapy goes to trial for multiple sclerosis.

Brugarolas P, Popko B - Neurol Neuroimmunol Neuroinflamm (2014)

Possible signaling pathways that anti-LINGO-1 antibody may modulateCellular specificity of these interactions remains to be fully elucidated.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4202671&req=5

Figure 1: Possible signaling pathways that anti-LINGO-1 antibody may modulateCellular specificity of these interactions remains to be fully elucidated.
Mentions: BIIB033 targets LINGO-1, a protein expressed in oligodendrocytes and neurons that has been shown to naturally inhibit oligodendrocyte differentiation and myelination.7 This protein was also found to have increased expression in oligodendrocyte precursors from MS lesions.8 These discoveries led to the hypothesis that LINGO-1 inhibitors may enhance remyelination, which was later demonstrated using an anti-LINGO-1 antibody in several animal models of demyelination.9 LINGO-1 is a leucine-rich repeat and immunoglobulin domain-containing Nogo receptor-interacting protein shown to interact with EGFR, ErB2, NgR1, and TrkB receptors in the CNS.8 BIIB033 is thought to disrupt some or all of these interactions, leading to the activation of pathways critical for myelination (figure).

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, The University of Chicago, Chicago, IL.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

A current thought in the MS therapeutics community is that drugs that enhance remyelination may be more effective in reducing long-term disability... This hypothesis is based on the observation that disability in MS increases with age as the capacity of oligodendrocytes to remyelinate decreases... Additional support for this hypothesis comes from extensive preclinical studies showing that promoting remyelination either by transplanting myelinating stem cells or by pharmacologic enhancement of endogenous myelination processes reduces clinical severity in animal models of MS... BIIB033 is thought to disrupt some or all of these interactions, leading to the activation of pathways critical for myelination (figure)... Most monoclonal antibodies, and BIIB033 is no exception, have low penetration into the CNS, which suggests that very high doses may be required to obtain a therapeutic effect... The researchers measured the concentration of BIIB033 in CSF and concluded that doses higher than 10 mg/kg may result in concentrations in the CNS equivalent to those shown to enhance remyelination in animal models of MS... One of the drawbacks of antibody therapies is that patients may develop an immune response against the therapeutic molecule, rendering the drug no longer useful in those patients... In this article, they evaluated the rate of production of antibodies against BIIB033 and found it to be low... While this is encouraging, in this study the patients received only 1 or 2 doses of the drug, which is not representative of the therapeutic paradigm in the long-term... Unfortunately, they also found antibodies against BIIB033 in one placebo-treated individual (false-positive), which indicates that a better assay may be needed... The phase II trial for BIIB033 will be carried out in combination with Avonex (interferon beta), which is one of the front-line anti-inflammatory MS drugs currently in use... Over the past decade considerable effort has been exerted to develop therapeutic strategies to enhance myelin repair... These attempts have been based largely on a significant body of data that has defined the intrinsic and extrinsic factors that drive oligodendrocyte maturation and the myelination process... The anti-LINGO-1 trial is likely the first of many that will test drugs that have been shown to enhance remyelination in murine models... Soon we should know whether this approach will provide benefit to patients with MS, which would be the first evidence that enhancing myelin repair may alter the course of this disease.

No MeSH data available.