RR Wang, Y Chen, T Guo, W Zhen, TB Guo, RY Zhao,
AA Liu1, JP Rubio, D Krull, J Lu, M Song, P Thompson,
S Wang1, JC Richardson.Histamine H3 receptor negatively regulates oligodendrocyte differentiation and myelination. ACTRIMS/ECTRIMS http://www.MSboston2014.org
Background: A huge unmet medical need exists in development
of new treatment paradigms to repair myelin in patients with multiple sclerosis (MS). Agents which can promote oligodendrocyte precursor cell (OPC) differentiation are considered to possess the potential to accelerate/restore halted remyelination in MS patients, but so far very few therapeutic targets have been identified.
Objectives: To identify novel targets to induce remyelination, we
established an in vitro differentiation assay with rat OPCs
to screen GSK-proprietary annotated libraries.
Methods: The compounds and related targets were then validated
through a series of in vitro and in vivo assays, i.e. cerebellar slice
assay, gene-based manipulation, cuprizone model and pathology
analysis with MS samples.
Results: Out of ~10,000 compounds screened, there were 21 hits
that promoted OPC myelin basic protein (MBP) expression in a
concentration-dependent manner, four of which were antagonists for the Gi/o-coupled receptor histamine H3 receptor (H3R). Further
testing of additional structurally-diverse H3R modulators revealed
that only inverse agonists but not neutral antagonists promoted oligodendrocyte differentiation and cerebellar slice myelination, which implied a key role of the constitutive activity of H3R. H3R was expressed in all stages of oligodendrocyte differentiation, and siRNA knock-down of H3R expression to ~40% of normal levels enhanced the expression of MBP and myelin associated glycoprotein (MAG), markers for mature oligodendrocytes. Furthermore, systemic administration of a brain-penetrable H3R inverse agonist, GSK247246 enhanced remyelination in the mouse cuprizone model. These data support that the constitutive activity of H3R negatively regulates oligodendrocyte differentiation. In humans, we detected oligodendroglial H3R expression in demyelinated MS lesions and observed genetic association between an exonic single nucleotide polymorphism in HRH3 and susceptibility to MS (p=0.006, OR=1.22). GSK239512 is a highly potent, selective, orally bioavailable and brain penetrant H3 receptor inverse agonist with a good safety/tolerability profile; when tested in myelination-relevant assays,GSK239512 demonstrated in vitro and in vivo efficacy in promoting oligodendrocyte differentiation and myelination.
Conclusions: From phenotypic screen to human genetics, we provide evidence for H3R as a novel therapeutic target for myelination, paving the way for clinical testing of GSK239512 in MS and other demyelinating diseases.
This is a study presented at ACTRIMS/ECTRIMS2014 and it may be published and require a new post…however it is pharma led study and so may never see the light of day. However I thought you may be interested in this.
This study reports the results from a “fishing trip” to find what causes repair. A “fishing trip” is basically a look-see experiment which has no a-priori view of what will happen and contrasts with the hypothesis driven research were you test an idea and see if it works. Grants generally get canned when applications for fishing trips are requested. However they are often needed to get the ideas to provide the hypothesis-driven research.
If you have an (automated) assay to show that a function that can be screen and a drug library (thousands upon thousands of compounds) and see what drugs fall out. You can work them up further to get a pharmaceutical drug.
This study demonstrates that a drug that inhibits the Histamine 3 receptor can promote remyelination in the test tube. This is expressed in human brain. This has been associated with susceptibility in EAE and it may also have some genetic influence on MS susceptibility, as shown here.
There are now 159 known MS susceptibility genes accounting for about half of the genetic susceptibility with about another 250 to be found.
Agonists stimulate receptors, antagonists block receptors and stop agonists from working, whereas inverse agonists deliver an negative inhibitory signal. In this study they found that an inverse agonist to Histamine 3 receptor promoted remyelination.
It is also interesting that another fishing expedition pulled out a Histamine H1 receptor anatagonist, which cold also influence acetyl choline. http://multiple-sclerosis-research.blogspot.co.uk/2014/07/a-quick-screen-to-find-myelination-drug.htmlseldom deliver unless Pharma is involved.
C Schwartzbach, R Grove, P Thompson, O Graff1, MA
Peykamian, K Harding, J Hilpert, R Brown, D Arnold. The effects of GSK239512 on lesion remyelination in a relapsing remitting MS population: design of a phase 2a imaging study.ACTRIMS/ECTRIMS http://www.MSboston2014.org
Background: GSK239512 is a potent, selective, orally bioavailable
and brain penetrant histamine 3 receptor (H3R) antagonist/
inverse agonist. In MS, evidence supports a failure of oligodendrocyte precursor cells (OPC) differentiation as the root cause of remyelination failure. Preclinical studies demonstrating H3R expression and activity on OPCs have indicated the potential for development of GSK239512 in MS.
Objectives: To present the design and preliminary subject disposition of a GSK-funded phase 2a study investigating the effect and safety of GSK239512 in promoting remyelination in patients with relapsing remitting MS (RRMS), using brain MRI assessments of magnetization transfer ratio (MTR) to detect lesion remyelination.
Methods: GSK study H3M116477 is a randomized, parallel group, placebo-controlled study (CT.gov identifier: NCT01772199). Subjects with RRMS ableto maintain stable background treatment (≥1 year prior to enrollment) with either Avonex (Interferon-beta1a) or Copaxone (Glatiramer Acetate) for the duration of the study were randomized in a 1:1 ratio between placebo and GSK239512 for a total treatment period of 48 weeks. The primary endpoint is the evaluation of mean changes in lesion myelination using two MTR endpoints comparing placebo to GSK239512 treated subjects: 1) New Gadolinium enhanced (GdE) lesion MTR differences (calibrated to reference scan) from before enhancement
to stable recovery (≥3 months post new GdE
lesion), and 2) New Delta MTR lesion MTR differences (calibrated to reference scan) from before lesion appearance to stable recovery
(≥3 months post lesion appearance). Secondary endpoints are designed to further evaluate the impact of GSK239512 on standard MRI, MS Clinical, and Safety measures.
Results: The study enrolled 131 patients, 18-50 years of age, with
RRMS (2010 revised McDonald criteria), an Expanded Disability
Status Scale (EDSS) score of 1.0-4.5, disease duration ≤10 years
and evidence of recent clinical disease activity (i.e., relapse or
lesion activity within the prior year).
Conclusions: Using changes in MTR, this study is designed to
establish the ability of GSK239512 to promote lesion remyelination. Secondary MRI and clinical endpoints will assist in data interpretation and in the design of future studies to interrogate the clinical benefit of lesion remyelination in RRMS patients.
So Pharma just get on an do it...
However this has risks of not working…is MTR sensitive enough to see sufficient remyelination. Shame electrophysiology does not seem to be mentioned in NCT01772199 . Those recruited for trials are large based in Eastern Europe. This is an add-on to current DMT.