Methods for treatment or prevention of neurodegenerative conditions using immunoisolatory implantable vehicles with a biocompatible jacket and a biocompatible matrix core

• US 5,871,767 A
• Filed: 05/24/1995
• Issued: 02/16/1999
• Est. Priority Date: 04/25/1991
• Status: Expired due to Term

• Current Assignee: Neurotech S.A. (LivaNova Plc)
• Original Assignee: Brown University
• Inventors: Emerich, Dwaine F., Aebischer, Patrick, Sanberg, Paul R., Dionne, Keith E., Lysaght, Michael J., Vasconcellos, Alfred V., Gentile, Frank T., Christenson, Lisa, Scharp, David W., Hegre, Orion D., Hoffman, Diane, Lacy, Paul E.
• Primary Examiner(s): Bawa, Raj
• Application Number:
  US08/449,062
• Time in Patent Office: 1,364 Days
• Field of Search: 424/422, 424/423, 424/426, 424/427, 424/430, 424/434, 424/437, 424/489, 424/490
• US Class Current: 424/422
• CPC Class Codes: A61K 2035/126 Immunoprotecting barriers, e.g. jackets, diffusion chambers
• CPC Class Codes: A61K 2035/128 capsules, e.g. microcapsules
• CPC Class Codes: A61K 35/12 Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells vaccines or medicinal preparations containing antigens or antibodies A61K39/00
• 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 35/39 Pancreas; Islets of Langerhans Langerhans cells of epidermis A61K35/36
• 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: 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 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61K 9/0092 Hollow drug-filled fibres, tubes of the core-shell type, coated fibres, coated rods, microtubules or nanotubes
• CPC Class Codes: A61K 9/4816 Wall or shell material
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/24 of the sex hormones
• CPC Class Codes: C12N 2510/02 : Cells for production
• CPC Class Codes: C12N 5/0012 : Cell encapsulation
• CPC Class Codes: C12N 5/0062 : General methods for three-dimensional culture
• CPC Class Codes: C12N 5/0614 : Adrenal gland
• CPC Class Codes: C12N 5/0656 : Adult fibroblasts
• CPC Class Codes: C12N 5/0677 : Three-dimensional culture, tissue culture or organ culture; Encapsulated cells

Abstract

A method for treatment of a neurodegenerative condition in a patient comprising implanting in the patient at least one immunoisolatory vehicle comprising a corc comprising a volume of at least 1 μl and at least 10⁴ living cells which secrete at least one biologically active product, said cells being dispersed in a biocompatible matrix comprising a hydrogel or extracellular matrix components, and an external jacket surrounding the core, the jacket comprising a biocompatible hydrogel or thermoplastic, the jacket being free of cells projecting externally thereof, said jacket having a molecular weight cutoff permitting the passage of the biologically active product from the core through the jacket.

Claims

1. A method for treatment a neurodegenerative condition in a patient comprising implanting in the patient at least one immunoisolatory vehicle comprising:

(a) a core comprising a volume of at least 1 μ

l and at least 10⁴ living cells which secrete at least one biologically active product, said cells being dispersed in a biocompatible matrix comprising a hydrogel or extracellular matrix components, and

(b) an external jacket surrounding the core, the jacket comprising a biocompatible hydrogel that does not ionically bond to a core, matrix material during formation of the jacket, the jacket being free of cells projecting externally thereof, said jacket having a molecular weight cutoff permitting passage of the biologically active product from the core through the jacket.

2. The method of claim 1 wherein said neurodegenerative condition is caused by neuroexcitotoxicity.

3. The method of claim 2 wherein said neuroexcitotoxicity is caused by glutamate or glutamate analogs.

4. The method of claim 1 wherein said neurodegenerative condition is Huntington'"'"'s disease or AIDS-related dementia.

5. The method of claim 1 wherein said neurodegenerative condition is cholinergic neuron degeneration.

6. The method of claim 1 wherein said neurodegenerative condition is Alzheimer'"'"'s disease.

7. The method of claim 1 wherein said cells comprise cells which have been genetically engineered to secrete recombinant nerve growth factor.

8. The method of claim 1 wherein said cells are selected from the group consisting of adrenal chromaffin cells, Schwann cells, glial cells, or astrocytes.

9. The method of claim 1 wherein said biologically active product is selected from the group consisting of nerve growth factor, basic fibroblast growth factor, ciliary neurotrophic factor, brain-derived neurotrophic factor, neurotrophin 3, and alpha neuroprotectin.

10. The method of claim 1 wherein said biocompatible matrix comprises extracellular matrix components.

11. The method of claim 10 wherein said components are selected from the group consisting of collagen, laminin, glycosaminoglycans, proteoglycans, fibronectin, elastin, and mixtures thereof.

12. The method of claim 11 wherein said glycosaminoglycans are selected from the group consisting of hyaluronic acid, chondroitin sulfate, heparin, and heparin sulfate.

26. The method of claim 1 or 13 wherein the biologically active product is a growth factor, a trophic factor, or both.

28. The method of claim 1 or 13 wherein the jacket further comprises a hydrophilic or hydrophobic additive.

29. The method of claim 1 or --wherein the core matrix comprises a hydrogel.

30. The method of claim 1 or 13 wherein the core matrix is selected from the group consisting of alginate, collagen, laminin-containing hydrogels, agarose, cellulose, methylcellulose block copolymer of ethylene-vinylalcohol, sodium polystyrene sulfonate, vinyl-methyl-tribenzyl ammonium chloride, phosphazene, and polyvinylalcohol.

31. The method of claim 1 or 13 wherein the biologically active product is selected from the group consisting of antibodies, enzymes, trophic factors, growth factors, hormones, biological response modifiers, cytokines, lymphokines and neurotransmitters.

32. The method of claim 1 or 13 wherein the biologically active product is a neurotransmitter.

33. The method of claim 1 or 13 wherein accessory cells are coisolated with the cells in the core.

34. The method of claim 1 or 13 wherein the cells are primary cells.

35. The method of claim 1 or 13 wherein the cells are selected from the group consisting of adrenal chromaffin cells, antibody-secreting cells, fibroblasts, astrocytes, and Chinese hamster ovary cells.

36. The method of claim 1 or 13 wherein the cells are neural stem cells.

37. The method of claim 1 or 13 wherein the cells are adrenal chromaffin cells.

38. The method of claim 1 or 13 wherein the core has a volume in excess of 10 μ

l.

39. The method of claim 1 or 13 wherein the jacket is between 5 and 200 μ

m thick.

40. The method of claim 1 or 13 wherein the jacket has a molecular weight cutoff is between 50 kD and 2000 kD.

41. The method of claim 1 or 13 wherein the jacket is shaped to form a hollow fiber.

42. The method of claim 1 or 13 wherein the jacket is shaped to form a flat sheet.

43. The method of claim 1 or 13 wherein more than one vehicle but fewer than ten vehicles are implanted in the patient.

44. The method of claim 1 or 13 wherein the cells are allogeneic or syngeneic to the patient.

45. The method of claim 1 or 13 wherein the patient is an aged individual.

13. A method for treatment of a neurodegenerative condition in a patient comprising implanting in the patient at least one immunoisolatory vehicle comprising:

(a) a core comprising a volume of at least 1 μ

l and at least 10⁴ living cells which secrete at least one biologically active product, said cells being dispersed in a biocompatible matrix comprising a hydrogel or extracellular matrix components, and

(b) an external jacket surrounding the core, the jacket comprising a biocompatible thermoplastic, the jacket being free of said cells projecting externally thereof, said jacket having a molecular weight cutoff permitting passage of the biologically active product from the core through the jacket into the patient'"'"'s body.

14. The method of claim 13 wherein said neural degeneration is associated with Parkinson'"'"'s disease.

15. The method of claim 13 wherein said neural degeneration is caused by neuroexcitotoxicity.

16. The method of claim 13 wherein said neuroexcitotoxicity is caused by glutamate or glutamate analogs.

17. The method of claim 13 wherein said neurodegenerative condition is Huntington'"'"'s disease or AIDS-related dementia.

18. The method of claim 13 wherein said neurodegenerative condition is cholinergic neuron degeneration.

19. The method of claim 13 wherein said neurodegenerative condition is Alzheimer'"'"'s disease.

20. The method of claim 13 wherein said cells comprise cells which have been genetically engineered to secrete recombinant nerve growth factor.

21. The method of claim 13 wherein said cells are selected from the group consisting of adrenal chromaffin cells, Schwann cells, glial cells, or astrocytes.

22. The method of claim 13 wherein said biologically active product is selected from the group consisting of nerve growth factor, basic fibroblast growth factor, ciliary neurotrophic factor, brain-derived neurotrophic factor, neurotrophin 3, and alpha neuroprotectin.

23. The method of claim 13 wherein said biocompatible matrix comprises extracellular matrix components.

24. The method of claim 23 wherein said components are selected from the group consisting of collagen, laminin, glycosaminoglycans, proteoglycans, fibronectin, elastin, and mixtures thereof.

25. The method of claim 24 wherein said glycosaminoglycans are selected from the group consisting of hyaluronic acid, chondroitin sulfate, heparin, and heparin sulfate.

27. The method of claim 13 wherein the jacket is selected from the group consisting of polyacrylonitrile-polyvinylchloride, polyacrylonitrile, polymethylmethacrylate, polyvinyldifluoride, polyolefins, polysulfones and celluloses.