Method for transplanting cells into the brain and therapeutic uses therefor

• US 6,060,048 A
• Filed: 06/02/1995
• Issued: 05/09/2000
• Est. Priority Date: 10/19/1990
• Status: Expired due to Term

• Current Assignee: New York University
• Original Assignee: New York University
• Inventors: Cherksey, Bruce D.
• Primary Examiner(s): Campell, Bruce R.
• Assistant Examiner(s): REYNOLDS, DEBORAH J
• Application Number:
  US08/460,706
• Time in Patent Office: 1,803 Days
• Field of Search: 424/93.21, 424/93.1, 424/93.2, 514/44
• US Class Current: 424/93.1
• CPC Class Codes: A61F 2/00 Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents as cosmetic articles, see the relevant subclasses, e.g. wigs, hair pieces, A41G3/00, A41G5/00; artificial nails A45D31/00; dental prostheses A61C13/00; materials for prostheses A61L27/00; artificial hearts A61M60/00; artificial kidneys A61M1/14
• CPC Class Codes: A61K 35/30 Nerves; Brain; Eyes; Corneal cells; Cerebrospinal fluid; Neuronal stem cells; Neuronal precursor cells; Glial cells; Oligodendrocytes; Schwann cells; Astroglia; Astrocytes; Choroid plexus; Spinal cord tissue
• CPC Class Codes: A61K 47/6923 the form being an inorganic particle, e.g. ceramic particles, silica particles, ferrite or synsorb
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• CPC Class Codes: A61K 9/0085 Brain, e.g. brain implants; Spinal cord
• CPC Class Codes: A61K 9/1676 having a drug-free core with discrete complete coating layer containing drug adsorbates of liquid drug formulations on inert powders without simultaneous granulation step A61K9/141; with further drug-free outer coating A61K9/5078; drug conjugated to non-active particles A61K47/6921
• CPC Class Codes: A61L 27/3804 characterised by specific cells or progenitors thereof, e.g. fibroblasts, connective tissue cells, kidney cells
• CPC Class Codes: A61L 27/3813 Epithelial cells, e.g. keratinocytes, urothelial cells
• CPC Class Codes: A61L 27/3821 Bone-forming cells, e.g. osteoblasts, osteocytes, osteoprogenitor cells
• CPC Class Codes: A61L 27/383 Nerve cells, e.g. dendritic cells, Schwann cells
• CPC Class Codes: A61L 27/3878 Nerve tissue, brain, spinal cord, nerves, dura mater
• CPC Class Codes: C12N 2502/08 cells of the nervous system
• CPC Class Codes: C12N 2531/00 Microcarriers
• CPC Class Codes: C12N 2533/12 Glass
• CPC Class Codes: C12N 5/0614 Adrenal gland
• CPC Class Codes: C12N 5/0618 Cells of the nervous system
• CPC Class Codes: C12N 5/0619 Neurons
• CPC Class Codes: C12N 5/0621 Eye cells, e.g. cornea, iris pigmented cells photoreceptors C12N5/062

Abstract

A method for grafting a cell in the brain of a mammalian subject is accomplished by attaching the cell to a support matrix so that the cell attaches to the matrix surface, and implanting the support matrix with the attached cell into the brain. Preferred support matrices are glass or plastic microbeads, either solid or porous, having a diameter from about 90 to about 125 μm. The method employs cells of different types, preferably cells of neural or paraneural origin, such as adrenal chromaffin cells. Also useful are cell lines grown in vitro. Cells not of neural or paraneural origin, such as fibroblasts, may also be used following genetic alteration to express a desired neural product such as a neurotransmitter or a neuronal growth factor. The method is used to treat neurological diseases such as Parkinson'"'"'s disease, Alzheimer'"'"'s disease, Huntington'"'"'s disease, epilepsy, and traumatic brain injury.

Claims

1. A method for providing a neurally-active molecule to a mammal comprising

introducing a multiplicity of supports containing an effective number of viable cells adhered to surfaces of the supports, wherein:

(a) the introduction is into the mammal'"'"'s brain or spinal cord;

(b) the supports are comprised of a matrix material and have diameters greater than 10 μ

m; and

(c) said cells provide said neurally active molecule for at least two months after said administration.

2. The method of claim 1, wherein said supports are comprised of a matrix material selected from the group consisting of glass, polystyrene, polypropylene, polyethylene, polycarbonate, polypentane, acrylonitrile polymer, nylon, magnetite, natural polysaccbaride, a modified polysaccaride gelatin and collagen, and wherein the matrix material is of the type that does not stimulate a toxic reaction when implanted into a brain or spinal cord of a 180-200 gram rat.

3. The method of claim 2, wherein the matrix material is glass.

4. The method of claim 2, wherein said cells are dopamine producing cells.

5. The method of claim 4, wherein said dopamine producing cells are selected from the group consisting of adrenal chromaffin cells and retinal pigment epithelial cells.

6. The method of claim 4, wherein said producing cells are retinal pigment epithelial cells and said support matrix is comprised of gelatin.

7. The method of claim 6, wherein the supports have a diameter of from about 90 μ

m to about 150 μ

m.

8. The method of claim 1, wherein the supports are cylindrical, ellipsoidal, or spherical in shape.

9. The method of claim 1, wherein the supports have diameters from about 90 μ

m to about 150 μ

m.

10. The method of claim 1, wherein the mammal is a human.

11. The method of claim 1, wherein said cells produce acetylcholine.

12. The method of claim 1, wherein said cells produce GABA, acetylcholine or a mixture thereof.

13. The method of claim 1, wherein said cells produce GABA or molecules that block excitatory amino acid pathways.

14. The method of claim 1, wherein the supports are comprised of gelatin.

15. The method of claim 14, wherein the supports have a diameter of from about 90 μ

m to about 150 μ

m.

16. A method for providing dopamine to a mammal comprising injecting a multiplicity of supports containing an effective number of viable cells adhered to surfaces of the supports, wherein:

(a) the introducing is into the mammal'"'"'s brain or spinal cord;

(b) the supports are comprised of a matrix material and have diameters greater than 10 μ

m; and

(c) said cells are derived from adrenal medulla tissue and secrete dopamine.

17. The method of claim 16, wherein thee supports are comprised of gelatin.

19. A method according to one of claims 4, 16, or 18, wherein the mammal is a human with Parkinson'"'"'s disease.

18. A method for providing dopamine to a mammal comprising:

injecting a multiplicity of supports containing an effective number of viable cells adhered to surfaces of the supports, wherein;

(a) the injecting is into the mammal'"'"'s brain or spinal cord;

(b) the supports are comprised of a matrix material and have diameters greater than 10 μ

m; and

(c) said cells are retinal pigment epithelial cells and secrete dopamine.

20. A method of transplanting cells into a mammal having a disease or dysfunction responsive to a neurally-active molecule, comprising introducing a multiplicity of supports containing an effective number of viable cells that secrete said neurally active molecule adhered to surfaces of the supports, wherein:

(a) the introducing is into the mammal'"'"'s brain or spinal cord;

(b) the supports are comprised of a matrix material and have diameters greater than 10 μ

m; and

(c) said cells survive for at least two months after said introduction.

21. The method of claim 20, wherein said supports are comprised of a matrix material selected from the group consisting of glass, polystyrene, polypropylene, polyethylene, polycarbonate, polypentane, acrylonitrile polymer, nylon, magnetite, natural polysaccharide, a modified polysaccaride gelatin and collagen, and wherein the matrix material is of the type that does not stimulate a toxic reaction when implanted into a brain or spinal cord of a 180-200 gram rat.

22. The method of claim 21 wherein the matrix material is glass.

23. The method of claim 21 wherein the matrix material is gelatin.

24. The method of claim 20, wherein the supports are cylindrical, ellipsoidal, or spherical in shape.

25. The method of claim 20, wherein the supports have diameters from about 90 μ

m to about 150 μ

m.

26. The method of claim 20, wherein the viable cells are selected from the group consisting of retinal pigment epithelial cells, human foreskin fibroblasts, chromaffin cells, cells of neural origin, cells of paraneural origin, cells engineered by somatic cell hybridization, cells derived from the adrenal medulla, and cells that are genetically altered to express neuronal growth factors, neurotransmitters, neuropeptides or enzymes involved in brain metabolism.

27. The method of claim 26, wherein the cells of neural origin are neural cell lines.

28. The method of claim 20, wherein said mammal is a human.

29. The method of claim 20, wherein said cells are dopamine producing cells.

30. The method of claim 20, wherein the disease or dysfunction is Parkinson'"'"'s disease.

31. The method of claim 20, wherein said dopamine producing cells are selected from the group consisting of adrenal chromaffin cells and retinal pigment epithelial cells.

32. The method of claim 20, wherein said dopamine producing cells are retinal pigment epithelial cells.

33. The method of claim 32, wherein the supports are comprised of gelatin.

34. The method of claim 33, wherein the supports have a diameter from about 90 μ

m to about 150 μ

m.

35. The method of claim 20, wherein the disease or dysfunction is Alzheimer'"'"'s disease.

36. The method of claim 35, wherein said cells produce acetylcholine.

37. The method of claim 20, wherein the disease or dysfunction is Huntington'"'"'s disease.

38. The method of claim 37, wherein said cells produce GABA, acetylcholine, or a mixture thereof.

39. The method of claim 20, wherein the disease or dysfunction is epilepsy.

40. The method of claim 39, wherein said cells produce GABA or molecules that block excitatory amino acid pathways.

41. A method for providing a neurally-active molecule to a mammal comprising introducing a multiplicity of supports containing an effective number of viable cells that provide said neurally-active molecule, adhered to surfaces of the supports, wherein:

(a) the introducing is into the mammal'"'"'s brain or spinal cord; and

(b) the supports are comprised of a matrix material and have diameters greater than 10 μ

m.

42. The method of claim 41, wherein said supports are comprised of a matrix material selected from the group consisting of glass, polystyrene, polypropylene, polyethylene, polycarbonate, polypentane, acrylonitrile polymer, nylon, magnetite, natural polysaccharide, a modified polysaccaride gelatin and collagen, and wherein the matrix material is of the type that does not stimulate a toxic reaction when implanted into a brain or spinal cord of a 180-200 gran rat.

43. The method of claim 42, wherein said cells are dopamine producing cells.

44. The method of claim 43, wherein said dopamine producing cells are selected from the group consisting of adrenal chromaffin cells and retinal pigment epithelial cells.

45. The method of claim 43, wherein said dopamine producing cells are retinal pigment epithelial cells.

46. The method of claim 45, wherein the supports have a diameter of from about 90 μ

m to 150 μ

m.

47. The method of claim 45, wherein the supports are comprised of gelatin.

48. The method of claim 42, wherein the matrix material is glass.

49. The method of claim 41, wherein the supports are cylindrical, ellipsoidal, or spherical in shape.

50. The method of claim 41, wherein the supports have diameters from about 90 μ

m to about 150 μ

m.

51. The method of claim 41, wherein the mammal is a human.

52. The method of claim 41, wherein said cells produce acetylcholine.

53. The method of claim 41, wherein said cells produce GABA, acetylcholine or a mixture thereof.

54. The method of claim 41, wherein said cells produce GABA or molecules that block excitatory amino acid pathways.

55. The method of claim 41, wherein the supports are comprised of gelatin.

56. The method of claim 55, wherein the supports have a diameter of from about 90 μ

m to about 150 μ

m.