There is presently no cure for multiple sclerosis (MS). Currently available immunomodulatory therapies do not modify the pathogenesis of axonal degeneration once it is established and are only partially effective in preventing permanent disability accumulation in MS patients. Identifying a drug that stimulates endogenous myelination and thereby prevents axon degeneration could theoretically halt disease progression. To this end we have recently discovered that treatment with an estrogen receptor (ER) 2 ligand diarylpropionitrile (DPN) can induce functional endogenous remyelination in experimental autoimmune encephalomyelitis (EAE). This is the first pharmacological agent that has been shown to activate remyelination and to reverse axon damage in the presence of inflammation. Treatment with the ER2 ligands would likely be very well tolerated in males and females as both reproductive behavior in females as well as breast and uterine endometrial cancer are mediated through ER1, not ER2. Guided by recently published and preliminary data we would like to make the transition from bench (treatment of EAE) to bedside (treatment of MS). The goal of these studies is to determine the viability, pharmacokinetics and toxicity of ER2 ligands (DPN-Tocris and SAR143953-Sanofi Aventis) required by the FDA to move the compounds forward into testing in humans and in the clinic. The goals of this study are: to determine the lowest dose of ER2 ligands that can effectively stimulate endogenous myelination and restore functional axon conduction;to assess the critical window of time during disease during which ER2 ligands can restore demyelinated and neurodegenerative axons in a mouse model of MS;and to conduct conventional toxicity studies in rat to determine the safety of the compound. The results obtained from the study will complete the preliminary steps in the pipeline for pre-clinical development necessary to begin clinical testing of treating with ER2 ligands to prevent demyelination and axon injury in the nervous system.
The goals of the proposed research are to analyze the minimum dose, timing, and duration of neuroprotective effect conferred by treatment with an estrogen receptor (ER)2 ligand in a mouse model of MS. The proposed research is relevant to public health because we are examining a putative therapeutic agent that stimulates endogenous myelination resulting in sparing of axons and clinical protection during demyelinating disease. Treatment with the ER2 ligand would likely be very well tolerated in males and females as both breast and uterine endometrial cancer are mediated through ER1, not ER2. In addition, ER2 ligand has no known toxicity and once tested could be rapidly moved from the laboratory bench to the bedside. The proposed research is relevant to the part of NIH's mission that pertains to the conceptualization, discovery, and preclinical evaluation of innovative therapeutics for nervous system disorders, with the goal of accelerating the development of new treatments for these diseases that will help to reduce the burdens of human disability.
Discl aim er: Please note that the following critiques were prepared by the reviewers prior to the Study Section meeting and are provided in an essentially unedited form. While there is opportunity for the reviewers to update or revise their written evaluation, based upon the group's discussion, there is no guarantee that individual critiques have been updated subsequent to the discussion at the meeting. Therefore, the critiques may not fully reflect the final opinions of the individual reviewers at the close of group discussion or the final majority opinion of the group. Thus the Resume and Summary of Discussion is the final word on what the reviewers actually considered critical at the meeting.
|Hasselmann, Jonathan P C; Karim, Hawra; Khalaj, Anna J et al. (2017) Consistent induction of chronic experimental autoimmune encephalomyelitis in C57BL/6 mice for the longitudinal study of pathology and repair. J Neurosci Methods 284:71-84|
|Khalaj, Anna J; Hasselmann, Jonathan; Augello, Catherine et al. (2016) Nudging oligodendrocyte intrinsic signaling to remyelinate and repair: Estrogen receptor ligand effects. J Steroid Biochem Mol Biol 160:43-52|
|Moore, Spencer M; Khalaj, Anna J; Kumar, Shalini et al. (2014) Multiple functional therapeutic effects of the estrogen receptor ? agonist indazole-Cl in a mouse model of multiple sclerosis. Proc Natl Acad Sci U S A 111:18061-6|
|Moore, S; Patel, R; Hannsun, G et al. (2013) Sex chromosome complement influences functional callosal myelination. Neuroscience 245:166-78|
|Kumar, Shalini; Patel, Rhusheet; Moore, Spencer et al. (2013) Estrogen receptor ? ligand therapy activates PI3K/Akt/mTOR signaling in oligodendrocytes and promotes remyelination in a mouse model of multiple sclerosis. Neurobiol Dis 56:131-44|
|Patel, Rhusheet; Moore, Spencer; Crawford, Daniel K et al. (2013) Attenuation of corpus callosum axon myelination and remyelination in the absence of circulating sex hormones. Brain Pathol 23:462-75|
|Khalaj, Anna J; Yoon, Jaehee; Nakai, Jaspreet et al. (2013) Estrogen receptor (ER) ? expression in oligodendrocytes is required for attenuation of clinical disease by an ER? ligand. Proc Natl Acad Sci U S A 110:19125-30|
|Moore, Spencer; Khalaj, Anna J; Yoon, Jaehee et al. (2013) Therapeutic laquinimod treatment decreases inflammation, initiates axon remyelination, and improves motor deficit in a mouse model of multiple sclerosis. Brain Behav 3:664-82|
|Bankston, Andrew N; Li, Wenqi; Zhang, Hui et al. (2013) p39, the primary activator for cyclin-dependent kinase 5 (Cdk5) in oligodendroglia, is essential for oligodendroglia differentiation and myelin repair. J Biol Chem 288:18047-57|