Glial cell line-derived neurotrophic factor

• US 6,221,376 B1
• Filed: 09/22/1997
• Issued: 04/24/2001
• Est. Priority Date: 09/20/1991
• Status: Expired due to Fees

• Current Assignee: Amgen Inc.
• Original Assignee: Amgen Inc.
• Inventors: Lin, Leu-Fen H., Lile, Jack, Collins, Franklin D., Doherty, Daniel H., Bektesh, Susan
• Primary Examiner(s): Kunz, Gary L.
• Assistant Examiner(s): Gucker, Stephen
• Application Number:
  US08/935,268
• Time in Patent Office: 1,310 Days
• Field of Search: 424/422, 424/423, 424/424, 424/486, 424/489, 424/491, 424/499, 530/350, 530/399, 514/2, 514/12, 514/21, 604/891.1, 935/66, 435/182
• US Class Current: 424/424
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 9/0085 Brain, e.g. brain implants; Spinal cord
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/26 Psychostimulants, e.g. nicotine, cocaine
• 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: C07K 14/475 Growth factors; Growth regulators
• CPC Class Codes: Y10S 530/809 Fused cells, e.g. hybridoma
• CPC Class Codes: Y10S 530/839 Nerves; brain

Abstract

A novel neurotrophic factor referred to as glial cell line-derived neurotrophic factor (GDNF) has been identified. Genes encoding GDNF have been cloned and sequenced. Methods and devices are disclosed for the delivery of GDNF using either an implantable cell which expresses human GDNF or a biocompatible semipermeable membrane containing genetically engineered cells which express and secrete the neurotrophic factor.

Claims

1. An implantable device for the delivery of glial cell line-derived neurotrophic factor polypeptide comprising:

a membrane; and

cells transformed to express and secrete a glial cell line-derived neurotrophic factor polypeptide comprising an amino acid sequence of SEQ ID NO;

4 or SEQ ID NO;

6, wherein said cells are encapsulated within said membrane,

said membrane being permeable to said glial cell line-derived neurotrophic factor polypeptide, and substantially impermeable to immune system materials which are detrimental to said cells.

2. The device of claim 1 wherein said cells are transformed to contain a heterologous expression regulatory element operatively linked to a nucleic acid sequence encoding said glial cell line-derived neurotrophic factor polypeptide.

3. The device of claim 1 wherein said glial cell line-derived neurotrophic factor polypeptide comprises an amino acid sequence as set forth in SEQ ID NO:

6.

4. An implantable device for the delivery of glial cell line-derived neurotrophic factor polypeptide comprising:

a membrane; and

one or more cells encapsulated within said membrane, comprising cells transformed to express and secrete glial cell line-derived neurotrophic factor polypeptide,

wherein said membrane is permeable to said glial cell line-derived neurotrophic factor polypeptide, and substantially impermeable to immune system materials which are detrimental to said cells, and

wherein said glial cell line-derived neurotrophic factor polypeptide comprises an amino acid sequence which is in excess of 70% identical to an amino acid sequence set forth in SEQ ID NO;

4 or SEQ ID NO;

6 when four gaps in a length of 100 amino acids may be introduced to assist in that alignment, and wherein said glial cell line-derived neurotrophic factor polypeptide has the ability to promote the survival or function of nerve cells.

5. A device of claim 4 wherein said cells contain an expression regulatory element operatively linked to a nucleic acid sequence encoding said glial cell line-derived neurotrophic factor polypeptide.

6. A device of claim 4 wherein said glial cell line-derived neurotrophic factor polypeptide comprises an amino acid sequence which is in excess of 70% identical to an amino acid sequence of SEQ ID NO:

6 when four gaps in a length of 100 amino acids may be introduced to assist in that alignment.

7. A device of claim 4 wherein said glial cell line-derived neurotrophic factor polypeptide comprises the amino acid sequence of SEQ ID NO:

6.

8. A device for the delivery of glial cell line-derived neurotrophic factor polypeptide, comprising:

a membrane; and

cells contained within said membrane, wherein said cells are recombinantly modified to express and secrete a glial cell line-derived neurotrophic factor polypeptide comprising the amino acid sequence of SEQ ID NO;

6, and

wherein said membrane is permeable to said glial cell line-derived neurotrophic factor polypeptide and substantially impermeable to immune system materials which are detrimental to said cells.

18. A device of claim 8 wherein said membrane is a polymeric membrane.

19. A device of claim 8 wherein said cells are human cells.

20. A device of claim 8 suitable for implantation in the central nervous system.

9. An article for the delivery of glial cell line-derived neurotrophic factor polypeptide, comprising:

one or more cells that have been transformed to express and secrete glial cell line-derived neurotrophic factor polypeptide wherein said glial cell line-derived neurotrophic factor polypeptide comprises an amino acid sequence set forth in SEQ ID NO;

4 or SEQ ID NO;

6 or a polypeptide which is in excess of 70% identical to an amino acid sequence set forth in SEQ ID NO;

4 or SEQ ID NO;

6 when four gaps in a length of 100 amino acids may be introduced to assist in that alignment, and wherein said glial cell line-derived neurotrophic factor polypeptide has the ability to promote the survival or function of nerve cells.

10. An article of claim 9 further comprising an implantable membrane in which said one or more cells are contained wherein said membrane is substantially impermeable to immune system materials which are detrimental to said cells.

11. An article of claim 9 wherein said polypeptide is in excess of 70% identical to the amino acid sequence of SEQ ID NO:

6 when four gaps in a length of 100 amino acids may be introduced to assist in that alignment.

12. An article for the delivery of glial cell line-derived neurotrophic factor polypeptide, comprising:

cells transformed to express and secrete glial cell line-derived neurotrophic factor polypeptide comprising the amino acid sequence of SEQ ID NO;

6 wherein said cells are suitable for implantation.

13. An article of claim 12 further comprising an implantable membrane in which said cells are contained, wherein said membrane is substantially impermeable to immune system materials which are detrimental to said cells.

14. An article of claim 12 further comprising an implantable polymeric membrane in which said cells are contained, wherein said membrane is substantially impermeable to immune system materials which are detrimental to said cells.

15. An article of claim 12 wherein said cells are human cells.

16. An article of claim 12 wherein said cells are suitable for implantation in the central nervous system.

17. A method of delivering glial derived neurotrophic factor polypeptide comprising implanting an article of claim 12.