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 increased myelination of nerves in a human subject having a demyelinating disease, the method comprising:
administering to the subject a muscarinic receptor antagonist as a neurotransmitter receptor modulating agent in an amount sufficient to stimulate oligodendrocyte precursor cell differentiation in the subject, thereby stimulating increased myelination of nerves in the subject,
wherein the muscarinic receptor antagonist is selected from benztropine, carbetapentane, clemastine, and salts thereof.
2. A method of stimulating increased myelination of nerves in a human subject having a demyelinating disease, the method comprising:
administering to the subject a dopamine receptor antagonist as a neurotransmitter receptor modulating agent in an amount sufficient to stimulate oligodendrocyte precursor cell differentiation in the subject, thereby stimulating increased myelination of nerves in the subject,
wherein the dopamine receptor antagonist is selected from benztropine, GBR12935, trifluoperazine, and salts thereof.
3. A method of stimulating increased myelination of nerves in a human subject having a demyelinating disease, the method comprising:
administering to the subject a neurotransmitter receptor modulating agent selected from the group consisting of a histamine receptor antagonist, a beta adrenergic receptor antagonist, and an opioid receptor modulator in an amount sufficient to stimulate oligodendrocyte precursor cell differentiation in the subject, thereby stimulating increased myelination of nerves in the subject,
wherein the histamine receptor antagonist is clemastine or a salt thereof, or
wherein the beta adrenergic receptor antagonist is salbutamol or a salt thereof, or
wherein the opioid receptor modulator is carbetapentane or a salt thereof.
4. The method of claim 1 , wherein the demyelinating disease is multiple sclerosis, idiopathic inflammatory demyelinating disease, transverse myelitis, Devic's disease, progressive multifocal leukoencephalopathy, optic neuritis, leukodystrophy, Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, autoimmune peripheral neuropathy, Charcot-Marie-Tooth disease, acute disseminated encephalomyelitis, adrenoleukodystrophy, adrenomyeloneuropathy, Leber's hereditary optic neuropathy, or HTLV-associated myelopathy.
5. The method of claim 4 , wherein the demyelinating disease is multiple sclerosis.
6. The method of claim 1 , wherein the subject has been administered an immunomodulatory agent.
7. The method of claim 6 , wherein the immunomodulatory agent is fingolimod (FTY720), interferon beta-1a, interferon beta-1b, glatiramer acetate, mitoxantrone, or natalizumab.
8. The method of claim 2 , wherein the demyelinating disease is multiple sclerosis, idiopathic inflammatory demyelinating disease, transverse myelitis, Devic's disease, progressive multifocal leukoencephalopathy, optic neuritis, leukodystrophy, Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, autoimmune peripheral neuropathy, Charcot-Marie-Tooth disease, acute disseminated encephalomyelitis, adrenoleukodystrophy, adrenomyeloneuropathy, Leber's hereditary optic neuropathy, or HTLV-associated myelopathy.
9. The method of claim 8 , wherein the demyelinating disease is multiple sclerosis.
10. The method of claim 2 , wherein the subject has been administered an immunomodulatory agent.
11. The method of claim 10 , wherein the immunomodulatory agent is fingolimod (FTY720), interferon beta-1a, interferon beta-1b, glatiramer acetate, mitoxantrone, or natalizumab.
12. The method of claim 3 , wherein the demyelinating disease is multiple sclerosis, idiopathic inflammatory demyelinating disease, transverse myelitis, Devic's disease, progressive multifocal leukoencephalopathy, optic neuritis, leukodystrophy, Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, autoimmune peripheral neuropathy, Charcot-Marie-Tooth disease, acute disseminated encephalomyelitis, adrenoleukodystrophy, adrenomyeloneuropathy, Leber's hereditary optic neuropathy, or HTLV-associated myelopathy.
13. The method of claim 12 , wherein the demyelinating disease is multiple sclerosis.
14. The method of claim 3 , wherein the subject has been administered an immunomodulatory agent.
15. The method of claim 14 , wherein the immunomodulatory agent is fingolimod (FTY720), interferon beta-1a, interferon beta-1b, glatiramer acetate, mitoxantrone, or natalizumab.
16. The method of claim 1 , wherein the muscarinic receptor antagonist is selected clemastine or a salt thereof.