Looking into the future: experimental studies of new therapiesFriday, October 04, 2013, 14:40 - 14:52
NDC-1308 induces remyelination in experimental models of multiple sclerosisS.H. Nye, S. Medicetty, B.D. Trapp, J.G. Yarger (Mequon, Cleveland, US)
Background: Previous reports using animal models of demyelinating diseases provided rationale for hormones as potential therapeutics to treat patients with multiple sclerosis (MS). Yet, while estrogens (like estriol) have advanced in clinical trials, they appear to impact only the neuroprotective aspects of MS, rather than remyelination. We investigated whether analogs of 17beta-estradiol (E2) could be created to remyelinate damaged axons in MS patients.
Objectives: A library of E2 analogs was assessed to: i) identify an analog of E2 with potent activity to differentiate oligodendrocyte progenitor cells (OPCs) into mature oligodendrocytes, ii) compare the potency of E2 analogs to other estrogens for their ability to remyelinate brain slices, and iii) determine whether a lead E2 analog can induce remyelination in different MS models.
Methods: E2 was modified with different C-6 alkoxyalkyl moieties and/or substitution of the C-18 methyl group. E2 analogs were characterized for estrogen receptor (ER) binding using recombinant human ERs, while ER activation was determined using luciferase reporter constructs. Differential gene expression of the E2 analogs was evaluated by microarray, followed by analysis of OPC differentiation/myelin synthesis pathways. Based on this data, a subset of E2 analogs was screened in vitro using OPCs (differentiation assay) and lysolethicin demyelinated brain slices (remyelination assay). A lead E2 analog (named NDC-1308) emerged and was formulated with cyclodextrin for proof-of-concept efficacy studies using the EAE and cuprizone mouse models.
Results: NDC-1308 preferentially activated ER-beta and was the most potent of the E2 analogs, causing a dramatic upregulation of genes (5 to 75-fold) in signaling pathways related to OPC differentiation and myelin production. NDC-1308 was significantly more potent at differentiating OPCs than estriol or E2 (P<0.05). Studies using demyelinated brain slices showed that NDC-1308 (3ÁM, 7 days), but not other estrogens, significantly enhanced remyelination. Cuprizone demyelinated mice showed a 20% increase in remyelination of hippocampal regions (P<0.01) following a 2-week treatment with NDC-1308 (50mg/Kg, i.p., QD). Prophylactic treatment of EAE mice with NDC-1308 (10mg/Kg, i.v., QD) delayed the onset and severity of disease for over 2 weeks. These results suggest that NDC-1308 can induce OPC differentiation leading to remyelination of damaged axons in vivo, along with a dual anti-inflammatory role.
Steven Nye and James Yarger are shareholders of ENDECE Neural, LLC
Satish Medicetty is a full time employee of Renovo Neural, Inc.
Bruce Trapp is a consulting Chief Scientific Officer of Renovo Neural. Dr. Trapp is also a consultant for Novartis and Biogen, and a member of the Speaker's Bureau for EMD Serono.
Renovo Neural,Inc. received compensation from ENDECE Neural,LLC to perform contracted research using the cuprizone experimental model. All personnel affiliated with Renovo Neural,Inc. do not have a conflicting interest in ENDECE Neural,LLC.