The therapeutic pyramid in MS; remyelination is only on level 3. #MSBlog #MSResearch
Epub: Mi et al. Blocking LINGO-1 as a Therapy to Promote CNS Repair: From Concept to the Clinic. CNS Drugs. 2013 May 17.
LINGO-1 is a leucine-rich repeat and Ig domain-containing, Nogo receptor interacting protein, selectively expressed in the CNS on both oligodendrocytes and neurons. Its expression is developmentally regulated, and is upregulated in CNS diseases and injury. In animal models, LINGO-1 expression is upregulated in rat spinal cord injury, experimental autoimmune encephalomyelitis, 6-hydroxydopamine neurotoxic lesions and glaucoma models. In humans, LINGO-1 expression is increased in oligodendrocyte progenitor cells from demyelinated white matter of multiple sclerosis post-mortem samples, and in dopaminergic neurons from Parkinson's disease brains. LINGO-1 negatively regulates oligodendrocyte differentiation and myelination, neuronal survival and axonal regeneration by activating ras homolog gene family member A (RhoA) and inhibiting protein kinase B (Akt) phosphorylation signalling pathways. Across diverse animal CNS disease models, targeted LINGO-1 inhibition promotes neuron and oligodendrocyte survival, axon regeneration, oligodendrocyte differentiation, remyelination and functional recovery. The targeted inhibition of LINGO-1 function presents a novel therapeutic approach for the treatment of CNS diseases.
"Lingo is a therapeutic target in MS and there is currently a clinical trial recruiting people presenting with optic neuritis. This trial is inhibiting the Lingo pathway with the aim of increasing myelination in damaged pathways. Dr Gordon Plant is the principal investigator in London and is recruiting ONers for this study. I am hopeful that this is trial will be the first to show that targeting remyelination is a valid target in MS. Anti-lingo or any other drug that promotes myelination still does get over the issue of inflammation. Myelination drugs will have to be used in combination with anti-inflammatory and possibly neuroprotective drugs. You need to have surviving axons to remyelinate. The strategy is therefore of a tiered approach as presented in the pyramid below."
: A Randomized, Double-Blind, Parallel-Group, Placebo Controlled Study to Assess the Efficacy, Safety, Tolerability, and Pharmacokinetics of BIIB033 in Subjects With First Episode of Acute Optic Neuritis
Primary Outcome Measures:
- Change in optic nerve conduction velocity (NCV) at Week 24 for the affected eye from the baseline of unaffected fellow eye as determined by full-field visual evoked potential (FF-VEP).
Secondary Outcome Measures:
- Change in thickness of the retinal nerve fiber layer (RNFL) at Week 24 for the affected eye from the baseline of unaffected fellow eye as determined by spectral-domain optical coherence tomography (SD-OCT).
- Change in thicknesses of the retinal ganglion cell layer/inner plexiform retinal layer (RGCL/IPL) at Week 24 for the affected eye from the baseline of unaffected fellow eye as determined by segmentation of SD-OCT.
- Change in low-contrast letter acuity (LCLA) at Week 24 from baseline as determined by 1.25% and 2.5% low contrast Sloan letter charts.
- Number of participants with Adverse events (AEs) and serious adverse events (SAEs)
- Population PK assessment as measured by Serum BIIB033 concentrations
- Ability to provide written consent and any authorization required by law.
- Aged 18 to 55 years old, inclusive, at the time of informed consent.
- Confirmed diagnosis of Acute Optic Neuritis (AON)
- All male or female subjects of childbearing potential must practice effective contraception during the study and be willing and able to continue contraception for at least 6 months after their last dose of study treatment.
- Prior episode(s) of optic neuritis or loss of vision not due to AON.
- Subjects with an established diagnosis of Multiple Sclerosis are excluded except if newly diagnosed based on the current episode of AON and positive brain MRI results consistent with the 2010 revisions to the McDonald's criteria.
- Previous history of a clinically significant disease.
- Females who have a positive pregnancy test result, or who are pregnant, breastfeeding, or planning to conceive during the study.
- History of human immunodeficiency virus (HIV), hepatitis C virus antibody, or hepatitis B virus.
- History or evidence of drug or alcohol abuse within 2 years prior to Screening.
- Current enrollment in any other study treatment or disease study within 3 months prior to Day 1/Baseline.
Labels: LINGO, remyelination, therapeutic pyramid