US5762926A
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US
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Method of grafting genetically modified cells to treat defects, disease or damage of the central nervous system
Assignee: University of California, San Diego
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Filing: 1995-06-05
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Granted: 1998-06-09
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Expires: 2015-06-05
Abstract
Abstract Methods of genetically modifying donor cells by gene transfer for grafting into the central nervous system to treat defective, diseased or damaged cells are disclosed. The modified donor cells produce functional molecules that effect the recovery or improved function of cells in the CNS. Methods and vectors for carrying out gene transfer and grafting are described.
Inventors
- 👤 Fred H. Gage
- 👤 Malcolm Schinstine
- 👤 Jasodhara Ray
- 👤 Theodore Friedmann
- 👤 Michael D. Kawaja
- 👤 Michael B. Rosenberg
- 👤 Jon A. Wolff
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-08 02:53
CPC Classifications
C; C12; C12N; C12N9/00; C12N9/10; C12N9/1025; C12N9/1029; A; A61; A61K; A61K35/00; A61K35/12; A61K35/33; A61K38/00; A61K38/04; A61K38/12; A61K38/13; A61K38/16; A61K38/17; A61K38/18; A61K38/1808; A61K38/1825; A61K38/185; A61K38/43; A61K38/44; C12N9/1048; C12N9/1077; C12Y; C12Y114/00; C12Y114/16; C12Y114/16002; C12Y203/00; C12Y203/01; C12Y203/01006; A61K48/00; Y; Y10; Y10S; Y10S435/00; Y10S435/8215; Y10S435/948
Claims Analysis
Total Claims: 52
Claim 1
Independent Claim
127 words
A method for treating defective, diseased or damaged cells in the mammalian central nervous system comprising grafting donor cells into the central nervous system of a subject, said subject or donor cells treated so as to minimize or reduce graft rejection, said donor cells genetically modified by insertion of at least one transgene encoding a product or products which directly or indirectly affect the cells into said cells to produce functional molecules in a sufficient amount to ameliorate said defective, diseased or damaged cells in the central nervous system, the transgene being selected from the group consisting of genes coding for tryptophan hydroxylase, GABA-decarboxylase, enkephalin, dopa decarboxylase (AADC), ciliary neuronal trophic factor (CNTF), brain derived neurotrophic factor (BDNF), neurotrophin (NT)-3, NT-4, and basic fibroblast growth factor (bFGF).
Claim 2
Independent Claim
127 words
A method for treating defective, diseased or damaged cells in the mammalian central nervous system comprising grafting donor cells into the central nervous system of a subject, said subject or donor cells treated so as to minimize or reduce graft rejection, said donor cells genetically modified by insertion of at least one transgene encoding a product or products which directly or indirectly affect the cells into said cells to produce functional molecules in a sufficient amount to ameliorate said defective, diseased or damaged cells in the central nervous system, the transgene being selected from the group consisting of genes coding for tryptophan hydroxylase, GABA-decarboxylase, enkephalin, dopa decarboxylase (AADC), ciliary neuronal trophic factor (CNTF), brain derived neurotrophic factor (BDNF), neurotrophin (NT)-3, NT-4, and basic fibroblast growth factor (bFGF).
Claim 3
Dependent Claim
24 words
The method of claim 1, wherein the step of grafting said donor cells comprises introducing said donor cells into the brain of a subject.
Claim 4
Dependent Claim
25 words
The method of claim 1, wherein the step of grafting said donor cells comprises introducing said donor cells into the spinal cord of a subject.
Claim 5
Dependent Claim
23 words
The method of claim 2, wherein said introducing comprises intracerebral, intraventricular, subdural space, putamen, nucleus basalis, hippocampus, cortex, striatal, caudate and intravenous introduction.
Claim 6
Dependent Claim
14 words
The method of claim 1, wherein said transgene is carried by a viral vector.
Claim 7
Dependent Claim
13 words
The method of claim 5, wherein said vector is a herpes virus vector.
Claim 8
Dependent Claim
13 words
The method of claim 5, wherein said vector is a neurotropic viral vector.
Claim 9
Dependent Claim
12 words
The method of claim 5, wherein said vector is a retroviral vector.
Claim 10
Dependent Claim
23 words
The method of claim 8, wherein said retroviral vector is the retroviral vector pLN.8PNL having a final construction as shown in FIG. 12.
Claim 11
Dependent Claim
23 words
The method of claim 8, wherein said retroviral vector is the retroviral vector pLThRNL having a final construction as shown in FIG. 16.
Claim 12
Dependent Claim
17 words
The method of claim 1, wherein the transgene is insert into donor cells by nonviral physical transfection.
Claim 13
Dependent Claim
17 words
The method of claim 11, wherein said nonviral physical transfection comprises microinjection of DNA encoding a transgene.
Claim 14
Dependent Claim
15 words
The method of claim 1, wherein the transgene is insert into donor cells by electroporation.
Claim 15
Dependent Claim
17 words
The method of claim 1, wherein the transgene is insert into donor cells by chemically mediated transfection.
Claim 16
Dependent Claim
14 words
The method of claim 14, wherein said chemically mediated transfection comprises calcium phosphate transfection.
Claim 17
Dependent Claim
17 words
The method of claim 1, wherein the transgene is insert into donor cells by liposomal mediated transfection.
Claim 18
Dependent Claim
15 words
The method of claim 1, wherein the transgene is insert into donor cells by lipofection.
Claim 19
Dependent Claim
32 words
The method of claim 1, wherein said molecules are selected from the group consisting of growth factors, enzymes, gangliosides, antibiotics, neurotransmitters, neurohormones, toxins, neurite promoting molecules, antimetabolites and precursors of said molecules.
Claim 20
Dependent Claim
23 words
The method of claim 1, further comprising co-administration of a therapeutic agent for treating said disease or damage to the central nervous system.
Claim 21
Dependent Claim
32 words
The method of claim 19, wherein said therapeutic agent is selected from the group consisting of growth factors, gangliosides, antibiotics, neurotransmitters, neurohormones, toxins, antimetabolites, neurite promoting molecules and precursors of these agents.
Claim 22
Dependent Claim
12 words
The method of claim 19, wherein said therapeutic agent is cellular matter.
Claim 23
Dependent Claim
26 words
The method of claim 21, wherein said cellular matter is selected from the group consisting of adrenal chromaffin cells, fetal brain tissue cells and placental cells.
Claim 24
Dependent Claim
28 words
The method of claim 1, further comprising implanting material to the site of said damage or disease, said material to facilitate reconnection or ameliorative interactions of injured neurons.
Claim 25
Dependent Claim
35 words
The method of claim 23, wherein said material is selected from the group consisting of homogenate of brain, homogenate of placenta, collagen, whole cells, synthetic material, neurite promoting extracellular matrix, and genetically modified donor cells.
Claim 26
Dependent Claim
42 words
The method of claim 1, wherein said donor cells are selected from the group consisting of fibroblasts, neurons, glial cells, keratinocytes, hepatocytes, ependymal cells, bone marrow cells, hippocampal cells, olfactory mucosa cells, stem cells, adrenal cells, connective cells, leukocytes and chromaffin cells.
Claim 27
Dependent Claim
19 words
The method of claim 1, wherein said donor cells comprise a mixture of cell types from different anatomical regions.
Claim 28
Dependent Claim
11 words
The method of claim 1, wherein said cells are primary cells.
Claim 29
Dependent Claim
11 words
The method of claim 1, wherein said cells are immortalized cells.
Claim 30
Dependent Claim
26 words
The method of claim 1, wherein the step of grafting said donor cells comprises grafting from approximately 10 4 to approximately 10 8 cells per graft.
Claim 31
Dependent Claim
23 words
The method of claim 1, wherein said donor cells consist of cells that have been passaged from approximately 2 to approximately 20 times.
Claim 32
Dependent Claim
22 words
The method of claim 1, wherein the step of grafting comprises multiple grafting of genetically modified donor cells in several different sites.
Claim 33
Dependent Claim
18 words
The method of claim 31, wherein said donor cells comprise a mixture of transgenes inserted into said cells.
Claim 34
Dependent Claim
15 words
The method of claim 31, wherein said donor cells comprise a mixture of cell types.
Claim 35
Dependent Claim
22 words
The method of claim 1, wherein the step of grafting comprises multiple grafting of genetically modified donor cells into a single site.
Claim 36
Dependent Claim
15 words
The method of claim 34, wherein said donor cells comprise a mixture of cell types.
Claim 37
Dependent Claim
23 words
The method of claim 5, wherein said vector carries a promoter to enhance expression of said transgene when said donor cells are quiescent.
Claim 38
Dependent Claim
12 words
The method of claim 36, wherein said promoter is a collagen promoter.
Claim 39
Dependent Claim
19 words
The method of claim 37, wherein said collagen promoter is selected from the group consisting of α1(I) and α2(I).
Claim 40
Dependent Claim
20 words
The method of claim 36, wherein said vector further carries an enhancer sequence to increase the activity of said promoter.
Claim 41
Dependent Claim
13 words
The method of claim 39, wherein said enhancer sequence is SV40 enhancer sequence.
Claim 42
Dependent Claim
15 words
The method of claim 39, wherein said enhancer sequence is a collagen promoter enhancer sequence.
Claim 43
Dependent Claim
15 words
The method of claim 41, wherein said enhancer sequence is a α2(I) collagen enhancer sequence.
Claim 44
Dependent Claim
18 words
The method of claim 36, further comprising the administration of cytokines to regulate the expression of said molecules.
Claim 45
Dependent Claim
33 words
The method of claim 43, wherein said cytokines are selected from the group consisting of interleukin-1β, interferon-α, tumor necrosis factor-α, tumor growth factors-β, basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF).
Claim 46
Dependent Claim
23 words
The method of claim 1, further comprising the use of growth factors to maintain survival of the donor cells in the mammalian CNS.
Claim 47
Dependent Claim
13 words
The method of claim 45, wherein said growth factors are bFGF or EGF.
Claim 48
Dependent Claim
23 words
The method of claim 1, further comprising regulation of the secretion of said functional molecules by administration of a precursor for said molecules.
Claim 49
Dependent Claim
16 words
The method of claim 47, wherein said functional molecules are acetylcholine, and said precursor is choline.
Claim 50
Dependent Claim
12 words
The method of claim 1, wherein said donor cells are primary fibroblasts.
Claim 51
Dependent Claim
12 words
The method of claim 49, wherein said donor cells are primate fibroblasts.
Claim 52
Dependent Claim
12 words
The method of claim 49, wherein said donor cells are human fibroblasts.
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USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 2001-06-08 | 2001-12-08 | 2002-06-09 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 2005-06-08 | 2005-12-08 | 2006-06-09 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 2009-06-08 | 2009-12-08 | 2010-06-09 | $7700.00 | Window Closed / Lapsed |