What do you all think of these studies of myelin repair?

A board to discuss future MS therapies in early stage (Phase I or II) trials.

What do you all think of these studies of myelin repair?

Postby ShirleyTemple » Fri Oct 02, 2015 7:22 pm

It may be better to read on link page, but i copy and pasted here as well http://thescrutinizer.net/repairing-mye ... sclerosis/

To stimulate myelin repair or remyelination in MS patients, researchers are focusing on approaches that promote OPC migration, survival, and maturation. The past several years of research have produced a number of druggable targets, which fall into two broad categories: molecules that negatively regulate OPC function and molecules that positively regulate OPC function (Table 1).

TARGET1 REFERENCES POTENTIAL THERAPEUTIC DRUG CLINICAL TRIAL2
SEMAPHORIN 4D
(SEMA4D) 17,18 ANTI-SEMA4D ANTIBODY
VX15/2503
(VACCINEX) PHASE 1
NCT01764737
LRR AND IG DOMAIN-CONTAINING, NOGO RECEPTOR-INTERACTING PROTEIN (LINGO-1) 19-21 ANTI-LINGO-1 ANTIBODY
BIIB033
(BIOGEN IDEC) PHASE 2
NCT01864148
SEMAPHORIN 3A
(SEMA3A) 15,22,23 NONE NO
ENDOTHELIN-1
(ET-1)/NOTCH 24 ET RECEPTOR ANTAGONIST
PD142,893 NO
MUSCARINIC RECEPTORS 25,26 ANTAGONISTS
CLEMASTINE FUMARATE
(TAVIST)
BENZTROPINE PHASE 2
NCT02040298
NO
OXIDATIVE STRESS 27 MITOCHONDRIA-TARGETED ANTI-OXIDANT MITOQUINONE (MITOQ) NOT FOR MS
PHASE 2 FOR PARKINSON’S DISEASE
NCT00329056
CXCR2 28 SMALL MOLECULE CXCR2 ANTAGONIST NO
? 29 MRF-008
FDA-APPROVED DRUG TO TREAT HYPERTENSION
(MYELIN REPAIR FOUNDATION) CLINICAL TRIAL IN PARTNERSHIP WITH THE NIH
ESTROGEN RECEPTOR 30,31 ESTROGEN RECEPTOR LIGANDS
NDC-1308
(ENDECE)
INDAZOLE CHLORIDE NONO
CONTACTIN-1 32 NONE NO
ACETYL-COA CARBOXYLASES (ACC1 AND ACC2) 34,35 HIGH-DOSE D-BIOTIN
MD1003
(MEDDAY) PHASE 3
NCT02220933
PLATELET-DERIVED GROWTH FACTOR RECEPTOR ALPHA (PDGFΑR) 36,37 RECOMBINANT HUMAN REMYELINATION PROMOTING IGM RHIGM22
(ACORDA) PHASE 1
NCT01803867
1Targets that are negative regulators of OPC function are highlighted in red, whereas those that are positive regulators are highlighted in green. How MRF-008 affects OPC function has not been disclosed; it is highlighted in white.

2Information obtained from ClinicalTrials.gov.

Although several targets have been identified in the myelin repair pathway, only six of them have potential therapeutic drugs that are being evaluated in clinical trials (Table 1). Two prospective therapeutic drugs are antibody antagonists, which block the activity of Semaphorin 4D (Sema4D) and LRR and Ig domain-containing, Nogo receptor-interacting protein (LINGO-1), both of which are negative regulators of OPC migration and maturation.17-21 Treating rodent models of demyelination with either the anti-Sema4D antibody or the anti-LINGO-1 antibody resulted in significant increases in the number of OPCs at demyelination sites and in the extent of remyelination compared to control-treated rodents.18-19 The anti-Sema4D antibody is currently being tested for safety and tolerability in a phase 1 trial while the anti-LINGO-1 antibody demonstrated tolerability and is now being tested in a phase 2 trial for safety and efficacy.

Recombinant human IgM (rHIgM22) is another antibody in clinical trials as a potential therapeutic drug for myelin repair; however, it acts as an agonist, not an antagonist. rHIgM22 binds and activates platelet-derived growth factor receptor alpha, a cell surface protein that provides OPCs with a signal to proliferate or increase in number.37 In a virus-induced model of demyelination, rHIgM22 treatment significantly increased the level of remyelination (59.7%) in relation to control treatment (15.8%).36 Phase 1 trials are underway to evaluate the safety and tolerability of rHIgM22.

Another druggable target in the myelin repair pathway is acetyl-CoA carboxylase, a biotin-dependent enzyme that synthesizes the fatty acids needed to produce myelin.34 High-dose biotin (MD1003), through its ability to enhance myelin lipid synthesis in oligodendrocytes, improved neurological symptoms in almost 90% (20/23) of the MS patients enrolled in a small, open-label study.34,35 Because of these findings, MD1003 has moved to a phase 3 trial.

The last two potential therapeutic drugs for myelin repair are drugs that are already in use to treat other medical conditions. MRF-008 is a generic drug for hypertension whose target in the remyelination pathway has not been disclosed.29 MRF-008 will be tested as a remyelination drug in a clinical trial in partnership with the National Institutes of Health.29 The other “repurposed” drug is clemastine (Tavist), an antihistamine that blocks both histamine and muscarinic receptors and that is used to treat allergies. Clemastine was identified in a high-throughput screen of 1000 compounds for its ability to induce OPC differentiation and oligodendrocyte myelination in culture.25 Its ability to promote remyelination was also assayed in a mouse demyelination model. This experiment showed that clemastine-treatment significantly increased both the kinetics and the extent of remyelination compared to control treatment.25 The effectiveness of clemastine as a remyelination drug is currently being evaluated in a phase 2 trial.

The combination of innovative thinking and new technology has led to the discovery of multiple strategies to remyelinate axons in MS patients. Within the next five years, after the completion of the clinical trials, we will know whether these remyelination strategies halt and possibly correct neurodegeneration. Because all forms of MS share a neurodegenerative phase, the results of these clinical trials may lead to therapeutic options for all patients with MS.
ShirleyTemple
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Posts: 36
Joined: Mon Sep 28, 2015 4:51 pm

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