Treatment of hearing impairments

• US 6,225,282 B1
• Filed: 01/02/1997
• Issued: 05/01/2001
• Est. Priority Date: 01/05/1996
• Status: Expired due to Term

• Current Assignee: Genentech, Inc. (Roche Holding AG)
• Original Assignee: Genentech, Inc. (Roche Holding AG)
• Inventors: Gao, Wei-Qiang
• Primary Examiner(s): Fay, Zohreh
• Application Number:
  US08/778,357
• Time in Patent Office: 1,580 Days
• Field of Search: 514/192, 514/198, 514/199, 514/2, 514/12
• US Class Current: 514/8.4
• CPC Class Codes: A61K 38/185 Nerve growth factor [NGF]; Brain derived neurotrophic factor [BDNF]; Ciliary neurotrophic factor [CNTF]; Glial derived neurotrophic factor [GDNF]; Neurotrophins, e.g. NT-3
• CPC Class Codes: C12N 2501/13 Nerve growth factor [NGF]; Brain-derived neurotrophic factor [BDNF]; Cilliary neurotrophic factor [CNTF]; Glial-derived neurotrophic factor [GDNF]; Neurotrophins [NT]; Neuregulins
• CPC Class Codes: C12N 2503/02 Drug screening
• CPC Class Codes: C12N 5/062 Sensory transducers, e.g. photoreceptors; Sensory neurons, e.g. for hearing, taste, smell, pH, touch, temperature, pain

Abstract

Compositions and methods are provided for prophylactic or therapeutic treatment of a mammal for hearing impairments involving neuronal damage, loss, or degeneration, preferably of spinal ganglion neurons, by administration of a therapeutically effective amount of a trkB or trkC agonist, particularly a neurotrophin, more preferably NT-4/5. Also provided are improved compositions and methods for treatments requiring administration of a pharmaceutical having an ototoxic side-effect, wherein the improvement includes administering a therapeutically effective amount of a trkB or trkC agonist to treat the ototoxicity.

Claims

1. A method for treating a hearing impairment in a mammal, comprising administering to the mammal in need of such treatment a therapeutically effective amount of a trkB or trkC agonist to promote post-natal spiral ganglia neuron protection of survival, wherein the agonist is selected from the group consisting of a neurotrophin, a chimeric neurotrophin, and a pantropic neurotrophin binding to and activating a trkB or trkC receptor, and an antibody agonist of a trkB or trkC receptor or antigen-binding fragment thereof, and wherein the hearing impairment is ototoxin induced.

2. The method of claim 1, wherein the agonist is a neurotrophin.

3. The method of claim 2, wherein the agonist is selected from the group consisting of NT-4/5, BDNF or NT-3.

4. The method of claim 3, wherein the agonist is NT-4/5.

5. The method of claim 1, wherein the ototoxin is a pharmaceutical drug.

6. The method of claim 5, wherein the pharmaceutical drug is selected from the group consisting of an aminoglycoside antibiotic, a chemotherapeutic agent, a salicylate or salicylate-like compound, a loop diuretic, and a quinine or quinine-like compound.

7. The method of claim 6, wherein the aminoglycoside antibiotic is selected from the group consisting of neomycin, paromomycin, ribostamycin, lividomycin, kanamycin, amikacin, tobramycin, viomycin, gentamicin, sisomicin, netilmicin, streptomycin, dibekacin, fortimicin, and dihydrostreptomycin.

8. The method of claim 6, wherein the ototoxic compound is an anti-neoplastic agent.

9. The method of claim 8, wherein the ototoxic compound is cisplatin or cisplatin-like compound.

10. The method of claim 1, wherein the trkB or trkC agonist is administered prior to onset of the hearing impairment.

11. The method of claim 1, wherein the trkB or trkC agonist is administered with an agent that promotes hair cell growth, proliferation, survival, or regeneration.

12. The method of claim 1, which further comprises administering of a second trkB or trkC agonist that complements the first agonist, wherein the second agonist is selected from the group consisting of a neurotrophin, a chimeric neurotrophin, and a pantropic neurotrophin binding to and activating a trkB or trkC receptor, and an antibody agonist of a trkB or trkC receptor or antigen-binding fragment thereof.

13. The method of claim 1, wherein the agonist comprises a chimeric or pantropic neurotrophin that agonizes at least trkB and trkC.

14. The method of claim 13, wherein the pantropic neurotrophin is MNTS-1.

22. The method of claims 5 to 11, wherein the agonist is NT-4/5 or BDNF.

15. A method of identifying a trkB or trkC agonist that provides post-natal spiral ganglion neuron protection or survival from an ototoxin, comprising

culturing a cochlear explant,

administering a candidate trkB or trkC agonist to the culture,

administering an ototoxin to the culture, and

determining the amount of protection or survival compared to a control culture to which the candidate trkB or trkC agonist was not administered.

16. A pharmaceutical composition comprising an ototoxic pharmaceutical agent capable of inducing a hearing impairment and a trkB or trkC agonist, which is present in an amount therapeutically effective for treating the hearing impairment to promote post-natal spiral ganglia neuron protection, wherein the agonist is selected from the group consisting of a neurotrophin, a chimeric neurotrophin, and a pantropic neurotrophin binding to and activating a trkB or trkC receptor, and an antibody agonist of a trkB or trkC receptor or antigen-binding fragment thereof.

17. The pharmaceutical composition of claim 16, wherein the ototoxic pharmaceutical agent is selected from the group consisting of an aminoglycoside antibiotic, a chemotherapeutic agent, a salicylate or salicylate-like compound, a loop diuretic, and a quinine or quinine-like compound.

18. The pharmaceutical composition of claim 16, further comprising a hair cell growth factor capable of promoting the growth, proliferation, regeneration, or survival of a hair cell.

23. The composition of claim 16, wherein the agonist is NT-4/5 or BDNF.

19. An improved method for treating a mammal with a pharmaceutical that causes a hearing impairment in the mammal, the improvement comprising administering a therapeutically effective amount of a trkB or trkC agonist to the mammal in need of such treatment to treat the ototoxin-induced hearing impairment to promote post-natal spiral ganglia neuron protection or survival, wherein the agonist is selected from the group consisting of a neurotrophin, a chimeric neurotrophin, and a pantropic neurotrophin binding to and activating a trkB or trkC receptor, and an antibody agonist of a trkB or trkC receptor or antigen-binding fragment thereof.

20. The method of claim 19, wherein the ototoxic pharmaceutical is selected from the group consisting of an aminoglycoside antibiotic, a chemotherapeutic compound, a salicylate or salicylate-like compound, a loop diuretic, and a quinine or quinine-like compound.

24. The method of claim 19, wherein the agonist is NT-4/5 or BDNF.

21. A method for promoting post-natal spiral ganglion neuron survival prior to, upon, or after exposure to an ototoxin that causes neuronal damage, loss, or degeneration, comprising administering to the neuron an effective amount of trkB or trkC agonist to promote post-natal neuron survival, wherein the agonist is selected from the group consisting of a neurotrophin, a chimeric neurotrophin, and a pantropic neurotrophin binding to and activating a trkB or trkC receptor, and an antibody agonist of a trkB or trkC receptor or antigen-binding fragment thereof.

25. The method of claim 21, wherein the agonist is NT-4/5 or BDNF.