Method of treating parkinson's disease in humans by convection-enhanced infusion of glial cell-line derived neurotrophic factor to the putamen

• US 8,946,152 B2
• Filed: 09/22/2005
• Issued: 02/03/2015
• Est. Priority Date: 02/24/2003
• Status: Active Grant

• Current Assignee: University Of Kentucky Research Foundation (University of Kentucky)
• Original Assignee: Amgen Inc., University Of Kentucky Research Foundation (University of Kentucky)
• Inventors: Gill, Steven S., Gash, Don M., Gerhardt, Greg Allen
• Primary Examiner(s): Emch, Gregory S
• Application Number:
  US11/664,943
• Publication Number:
  US 20110245798A1
• Time in Patent Office: 3,421 Days
• Field of Search: 530/300, 530/350, 514/17.7, 514/18.2, 514/6.9, 514/7.6, 514/8.3, 514/8.4, 514/17.8, 514/19.3, 514/1.1, 514/21.2, 514/5.2, 514/9.1, 435/375, 536/23.5, 604/500
• US Class Current: 514/8.3
• 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: A61P 25/16 Anti-Parkinson drugs

Abstract

A method of treating Parkinson'"'"'s disease in humans is disclosed, wherein glial cell-line derive neurotrophic factor (GDNF) is chronically administered directly to one or both putamen of a human in need of treatment thereof via convection-enhanced infusion using at least one implantable pump and at least one catheter. In one aspect of the present invention the GDNF is infused directly into one or both putamen through one or more indwelling intraparenchymal mutitiport brain catheters connected to one or moreimplantable pumps wherein the flow rate is pulsed.

Claims

1. A method of treating Parkinson'"'"'s disease in a human that comprises administering to a putamen of a human in need thereof via convection-enhanced infusion using a catheter implanted in the putamen providing localized and targeted delivery into the putamen a pharmaceutical composition comprising a pharmaceutically effective amount of a glial cell-line derived neurotrophic factor (GDNF) protein and a pharmaceutically acceptable vehicle, excipient, or diluent, wherein the GDNF protein is administered in an amount and over a time period effective to produce a sustained increase in dopamine uptake in the putamen, and wherein diffusion of said GDNF protein is limited to the putamen of said human.

2. A method of treating Parkinson'"'"'s disease in a human that comprises:

assessing dopaminergic function in a putamen of the human, pre-operatively;

identifying a site of dopaminergic dysfunction within the putamen;

administering to the putamen of the human via convection-enhanced infusion using a catheter implanted in the putamen providing localized and targeted delivery into the putamen a pharmaceutical composition comprising a pharmaceutically effective amount of a glial cell-line derived neurotrophic factor (GDNF) protein and a pharmaceutically acceptable vehicle, excipient, or diluent wherein the GDNF protein is administered in an amount and over a time period effective to produce a sustained increase in dopamine uptake in the putamen, and wherein diffusion of said GDNF protein is limited to the putamen of said human; and

,

optionally, assessing dopaminergic function within the putamen post-operatively.

3. The method of claim 2 wherein the GDNF protein is r-metHuGDNF.

4. The method of claim 3 wherein the vehicle, excipient, or diluent comprises (i) sodium chloride and sodium citrate, (ii) artificial cerebrospinal fluid (CSF), or (iii) sodium chloride, sodium citrate, and artificial CSF.

5. The method of claim 2, wherein assessing dopaminergic function comprises assessing dopamine uptake or dopamine storage.

6. The method of claim 5, wherein the site of dopaminergic dysfunction is the postero-dorsal region of the putamen.

7. The method of claim 5 wherein the site of dopaminergic dysfunction is the central region of the putamen.

8. A method of increasing function of dopaminergic neurons in a human in need thereof that comprises administering to a putamen of the human in need thereof via convection-enhanced infusion using a catheter implanted in the putamen providing localized and targeted delivery into the putamen a pharmaceutical composition comprising a pharmaceutically effective amount of a glial cell-line derived neurotrophic factor (GDNF) protein and a pharmaceutically acceptable vehicle, excipient, or diluent, wherein the GDNF protein is administered in an amount and over a time period effective to produce a sustained increase in dopamine uptake in the putamen, and wherein diffusion of said GDNF protein is limited to the putamen of said human.

9. A method of increasing uptake of dopamine by dopaminergic neurons in a human in need thereof that comprises administering to a putamen of the human in need thereof via convection-enhanced infusion using a catheter implanted in the putamen providing localized and targeted delivery into the putamen a pharmaceutical composition comprising a pharmaceutically effective amount of a glial cell-line derived neurotrophic factor (GDNF) protein and a pharmaceutically acceptable vehicle, excipient, or diluent, wherein diffusion of said GDNF protein is limited to the putamen of said human.

10. The method of claim 9 wherein the GDNF protein product is r-metHuGDNF.

11. The method of claim 10 wherein the vehicle, excipient, or diluent comprises (i) sodium chloride and sodium citrate, (ii) artificial cerebrospinal fluid (CSF), or (iii) sodium chloride, sodium citrate, and artificial CSF.

12. The method of claim 11, wherein the pharmaceutical composition is administered to the postero-dorsal region of the putamen.

13. The method of claim 11, wherein the pharmaceutical composition is administered to the central region of the putamen.

14. A method of regenerating dopaminergic neurons in a human in need thereof that comprises administering to a putamen of the human in need thereof via convection-enhanced infusion using a catheter implanted in the putamen providing localized and targeted delivery into the putamen a pharmaceutical composition comprising a pharmaceutically effective amount of a glial cell-line derived neurotrophic factor (GDNF) protein and at least one pharmaceutically acceptable vehicle, excipient, or diluent, wherein diffusion of said GDNF protein is limited to the putamen of said human.

21. The method of claim 2, 8, 9, 14, 15, 16, or 17 wherein the GDNF protein is administered at a dosage from about 1 μ

g/putamen/day to about 100 μ

g/putamen/day.

24. The method according to any one of claims 2, 8, 9, 14, 15, 16, 17, 22, and 23, wherein the administration of said pharmaceutical composition is pulsed.

15. A method of protecting dopaminergic neurons susceptible to degeneration in a human that comprises administering to a putamen of a human in need thereof via convection-enhanced infusion using a catheter implanted in the putamen providing localized and targeted delivery into the putamen a pharmaceutical composition comprising a pharmaceutically effective amount of a glial cell-line derived neurotrophic factor (GDNF) protein and a pharmaceutically acceptable vehicle, excipient, or diluent, wherein diffusion of said GDNF protein is limited to the putamen of said human.

16. A method of treating Parkinson'"'"'s disease in a human that comprises administering to a region of a putamen of a human in need thereof via convection-enhanced infusion using a catheter a pharmaceutical composition comprising a pharmaceutically effective amount of a glial cell-line derived neurotrophic factor (GDNF) protein and a pharmaceutically acceptable vehicle, excipient, or diluent, wherein diffusion of said GDNF protein is limited to the putamen of said human.

17. A method of treating Parkinson'"'"'s disease in a human that comprises administering to a putamen of a human in need thereof via convection-enhanced infusion using a catheter implanted in the putamen providing localized and targeted delivery into the putamen a pharmaceutical composition comprising a pharmaceutically effective amount of a glial cell-line derived neurotrophic factor (GDNF) protein and a pharmaceutically acceptable vehicle, excipient, or diluent, wherein diffusion of said GDNF protein is limited to the putamen of said human.

18. The method of claim 17 wherein the GDNF protein is r-metHuGDNF.

19. The method of claim 17, wherein the pharmaceutical composition is administered to the postero-dorsal region of the putamen.

20. The method of claim 17, wherein the pharmaceutical composition is administered to the central region of the putamen.

22. A method of producing a sustained increase in dopamine uptake within a putamen in a human suffering from Parkinson'"'"'s disease, the method consisting essentially of the step of administering to the putamen of a human in need thereof via convection-enhanced infusion using a catheter implanted in the putamen providing localized and targeted delivery into the putamen a pharmaceutical composition comprising a pharmaceutically effective amount of a glial cell-line derived neurotrophic factor (GDNF) protein and a pharmaceutically acceptable vehicle, excipient, or diluent, wherein the GDNF protein is administered in an amount and over a time period effective to produce a sustained increase in dopamine uptake in the putamen, and wherein diffusion of said GDNF protein is limited to the putamen of said human.

23. A method of producing a sustained increase in dopamine uptake within a putamen in a human suffering from Parkinson'"'"'s disease, the method consisting of the step of administering to the putamen of a human in need thereof via convection-enhanced infusion using a catheter implanted in the putamen providing localized and targeted delivery into the putamen a pharmaceutical composition comprising a pharmaceutically effective amount of a glial cell-line derived neurotrophic factor (GDNF) protein and a pharmaceutically acceptable vehicle, excipient, or diluent, wherein the GDNF protein is administered in an amount and over a time period effective to produce a sustained increase in dopamine uptake in the putamen, and wherein diffusion of said GDNF protein is limited to the putamen of said human.