Directed differentiation of oligodendrocyte precursor cells to a myelinating cell fate
The present invention provides methods of inducing differentiation of oligodendrocyte progenitor cells to a mature myelinating cell fate with a neurotransmitter receptor modulating agent. The present invention also provides methods of stimulating increased myelination in a subject in need thereof by administering said neurotransmitter receptor modulating agent. Methods of treating a subject having a demyelinating disease using a neurotransmitter receptor modulating agent are also provided.
1. A method of stimulating remyelination in a human subject having a demyelinating disease, the method comprising:
(a) identifying a human subject diagnosed with the demyelinating disease and being treated with an immunomodulatory agent; and
(b) administering to the human subject an effective amount of a muscarinic receptor antagonist to stimulate remyelination in the human subject, wherein the muscarinic receptor antagonist is selected from atropine, carbetapentane, clemastine, dicylomine, diphemanil, glycopyrrolate, ipratropium, methantheline, methylatropine, octatropine, propiverine, scopolamine, tiotropium, and salts thereof.
2. The method of claim 1 , wherein the muscarinic receptor antagonist is clemastine.
3. The method of claim 1 , wherein the immunomodulatory agent is fingolimod (FTY720), interferon beta-1a, interferon beta-1b, glatiramer acetate, mitoxantrone, or a monoclonal antibody.
4. The method of claim 1 , wherein the immunomodulatory agent is fingolimod (FTY720), interferon beta-1a, interferon beta-1b, glatiramer acetate, or mitoxantrone.
5. The method of claim 3 , wherein the immunomodulatory agent is selected from an interferon-1b and fingolimod.
6. The method of claim 3 , wherein the immunomodulatory agent is a monoclonal antibody selected from the group consisting of natalizumab, rituximab, daclizumab, and alemtuzumab.
7. The method of claim 1 , wherein the immunomodulatory agent is administered at a subtherapeutic dose and administration of the muscarinic receptor antagonist can enhance the effect of the immunomodulatory agent.
8. The method of claim 1 , wherein:
(i) each of the immunomodulatory agent and the muscarinic receptor antagonist is administered at a therapeutically effective dose; or
(ii) the muscarinic receptor antagonist is administered at a therapeutically effective dose and the immunomodulatory agent is administered at a subtherapeutic dose; or
(iii) each of the immunomodulatory agent and the muscarinic receptor antagonist is administered at a subtherapeutic dose.
9. The method of claim 1 , wherein the immunomodulatory agent and the muscarinic receptor antagonist are administered systemically.
10. The method of claim 1 , wherein the immunomodulatory agent and the muscarinic receptor antagonist are administered sequentially.
11. The method of claim 1 , wherein the immunomodulatory agent and the muscarinic receptor antagonist are administered concurrently.
12. The method of claim 1 , wherein the demyelinating disease is multiple sclerosis.
13. The method of claim 1 , wherein the method stimulates oligodendrocyte precursor cell differentiation.