Schwann cell bridge implants and phosphodiesterase inhibitors to stimulate CNS nerve regeneration

• US 20030220280A1
• Filed: 02/07/2003
• Published: 11/27/2003
• Est. Priority Date: 02/07/2002
• Status: Abandoned Application

• Current Assignee: Damien Daniel Pearse, Mary Bartlett Bunge
• Original Assignee: Damien Daniel Pearse, Mary Bartlett Bunge
• Inventors: Pearse, Damien Daniel, Bunge, Mary Bartlett
• Application Number:
  US10/359,554
• Publication Number:
  US 20030220280A1
• Time in Patent Office: Days
• US Class Current: 514/44
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/4015 having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
• CPC Class Codes: A61K 31/4706 4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/522 having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
• CPC Class Codes: A61K 31/7076 containing purines, e.g. adenosine, adenylic acid
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The use of a composition that elevates intracellular levels of cyclic nucleotide cyclases in combination with phosphodiesterase inhibitors and cell grafts to restore function after CNS injury.

Claims

1. A method of treating an animal following injury to an area of the animal'"'"'s central nervous system, the method comprising:

a) administering a cyclic nucleotide phosphodiesterase inhibitor to the animal;

b) administering a composition that elevates intracellular levels of a cyclic nucleotide cyclase to the animal; and

c) implanting cells that provide or mimic the functions of neural cells native to the animal’

s nervous system,

so that motor and/or sensory function is improved in the animal.

2. The method of claim 1 wherein the phosphodiesterase inhibitor is administered prior to the composition that elevates intracellular levels of a cyclic nucleotide cyclase.

3. The method of claim 1 wherein the phosphodiesterase inhibitor is administered simultaneously with the composition that elevates intracellular levels of a cyclic nucleotide cyclase.

4. The method of claim 1 wherein the phosphodiesterase inhibitor is administered systemically.

5. The method of claim 1 wherein the phosphodiesterase inhibitor is administered locally in the area of the injury.

6. The method of claim 1 wherein the composition that elevates intracellular levels of a cyclic nucleotide cyclase is administered locally in the area of the injury.

7. The method of claim 1 wherein the step of administering a cyclic nucleotide phosphodiesterase inhibitor comprises administering one or more compounds selected from the group consisting of rolipram, 3-isobutyl-1-methylxanthine (IBMX), 2-propyloxyphenyl)-8-azapurin-6-one (zaprinast), N-(3,5-dichlorpyrid-4-yl)-3-cyclopentyl-oxy-4-methoxy-benzamide (RPR-73401), 8-methoxy-5-N-propyl-3-methyl-1-ethyl-imidazo[1,5-a]-pyrido[3,2-e]-pyrazinone (D-22888), methyl-2-(4-aminophenyl)-1,2-dihydro-1-oxo-7-(2-pyridinylmethoxy)-4-(3,4,5-trimethoxyphenyl)-3-isoquinoline carboxylate sulfate (T-1032), 4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone (Ro-20-1724), 4-(3-chlorophenyl)-1,7-diethylpyrido[2,3-d]pyrimidin-2(1H)-one (YM976), N-cyclohexyl′

N-methyl-4-(1,2-dihydro-2-oxo-6-quinolyloxy) butyramide (cilostamide), dipyridamole, milrinone, amrinone, olprinone, pentoxifylline, theophylline, cilostazol, sildenafil and nimesulide.

8. The method of claim 1 wherein the step of administering a cyclic nucleotide phosphodiesterase inhibitor comprises administering an antisense sequence or vector designed to be complementary to, and prevent the processing of, the mRNA of a cyclic nucleotide phosphodiesterase.

9. The method of claim 1 wherein the step of administering a cyclic nucleotide phosphodiesterase inhibitor comprises administering rolipram.

10. The method of claim 9 wherein the dosage of rolipram is between 0.5 mg/kg and 200 mg/kg per day.

11. The method of claim 1 wherein the step of administering a composition that elevates intracellular levels of a cyclic nucleotide cyclase comprises administering one or more compounds selected from the group consisting of db-cAMP, 8-bromo-adenosine 3′

,5′

-monophosphate (8-Br-cAMP), 8-(4-chlorophenylthio)-cAMP, 8-chloro-adenosine 3′

,5′

-monophosphate (8-Cl-cAMP), dioctanoyl-cAMP, Sp-cAMPS, Sp-8-bromo-cAMPS, 8-br-cGMP, dibutyryl-cGMP and 8-(4-chlorophenylthio)-cGMP.

12. The method of claim 1 wherein the step of administering a composition that elevates intracellular levels of a cyclic nucleotide cyclase comprises administering db-cAMP.

13. The method of claim 12 wherein the dosage of db-cAMP is between 1 mg and 1000 mg per day.

14. The method of claim 1 wherein the step of implanting cells comprises implanting one or more cell types selected from the group consisting of Schwann cells, neural stem cells, neural precursor cells, neural progenitor cells, neurosphere cells, mesenchymal stem cells, hematopoietic stem cells, glial-restricted precursor cells, embryonic stem cells, bone marrow stromal cells and olfactory ensheathing glial cells.

15. The method of claim 1 wherein the step of implanting cells comprises transplanting Schwann cells.

16. The method of claim 15 wherein the step of implanting cells comprises injecting Schwann cells.

17. The method of claim 15 wherein the step of implanting cells comprises implanting a Schwann cell bridge.

18. The method claim 1 wherein the step of implanting cells comprises implanting an autograft.

19. The method of claim 1 wherein the step of implanting cells comprises implanting an allograft.

20. The method of claim 1 wherein the step of implanting cells comprises implanting a homograft.

21. The method of claim 1 wherein the step of implanting cells comprises implanting a xenograft.

22. The method of claim 1 wherein said animal is a mammal.

23. The method of claim 22 wherein said mammal is human.

24. A method of treating an animal following injury to a area in the animal'"'"'s central nervous system, the method comprising:

a) implanting Schwann cells at the site of central nervous system injury;

b) administering rolipram to the animal; and

c) administering dibutyryl-cAMP to the area of the injury during the step of administering rolipram.

25. A pharmaceutical composition comprising an effective amount of a phosphodiesterase inhibitor and a compound that elevates intracellular levels of a cyclic nucleotide cyclase.

26. The composition of claim 25 that additionally comprises an effective amount of cells having neural function.