Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2001-10-26
2004-11-09
Chen, Shin-Lin (Department: 1632)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C435S320100, C435S455000, C424S093200, C424S093210, C536S023500
Reexamination Certificate
active
06815431
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to methods for treatment of neurodegenerative disease and methods for delivery of therapeutic neurotrophins into the mammalian brain.
HISTORY OF THE RELATED ART
Neurotrophins play a physiological role in the development and regulation of neurons in mammals. In adults, basal forebrain cholinergic neurons, motor neurons and sensory neurons of the CNS retain responsiveness to neurotrophic factors and can regenerate after loss or damage in their presence. For this reason, neurotrophins are considered to have great promise as drugs for the treatment of neurodegenerative conditions such as Alzheimer's Disease (AD), Parkinson's Disease (PD), amyotrophic lateral sclerosis (ALS), peripheral sensory neuropathies and spinal cord injuries.
Direct delivery of neurotrophins through infusion into the neurocompromised brain has been met with limited success and, in one instance, actually worsened the condition being treated (Kordower, et al.,
Ann. Neurol
., 46:419-424, 1999 [symptoms of PD worsened following infusion of glial cell-derived neurotrophic factor]). In contrast, in vivo transduction of CNS cells with a neurotrophin encoding expression vector holds tremendous promise as a more broadly applicable method of treating and preventing neurodegeneration. Ideally, the vector utilized to deliver the neurotrophin will display at least moderate levels of transduction efficiency, while producing minimal toxicity.
SUMMARY OF THE INVENTION
The invention provides a lentiviral-based, clinically useful system and protocol for delivery of recombinant neurotrophins into the mammalian brain. The invention is particularly useful in treating neurodegenerative conditions in primates, in whom neurotrophins delivered according to the invention stimulate growth of neurons and recovery of neurological function.
More specifically, the invention consists of methods for intraparenchymal delivery of neurotrophins to defective, diseased or damaged cells in the mammalian brain using a lentiviral expression vector. In one aspect, the invention provides a specific protocol for use in genetically modifying target neurons (“target cells”) to produce a therapeutic neurotrophin; e.g., in the substantia nigra or basal forebrain. The genetic modification of target cells is achieved by in vivo transfection of neurons targeted for treatment, or by transfection of cells neighboring these target neurons (neurons or glia), with a recombinant expression vector for expression of the desired neurotrophin in situ.
The location for delivery of individual unit dosages of neurotrophin into the brain is selected for proximity to previously identified defective, diseased or damaged target cells in the brain. To intensify exposure of such target cells to the endogenous growth factors, each delivery site is situated no more than about 500 &mgr;m from a targeted cell and no more than about 10 mm from another delivery site. The total number of sites chosen for delivery of each unit dosage of neurotrophin will vary with the size of the region to be treated.
Optimally, for delivery of neurotrophin using the lentiviral expression vector, each unit dosage of neurotrophin will comprise 2.5 to 25 &mgr;l of an expression vector composition, wherein the composition includes a viral expression vector in a pharmaceutically acceptable fluid (“neurotrophic composition”) and provides from 10
10
up to 10
15
NGF expressing viral particles per ml of neurotrophic composition.
This lentiviral based protocol for neurotrophin delivery achieves a high level of transduction efficiency, with minimal toxicity, to produce a therapeutic or preventative effect in the primate brain.
REFERENCES:
patent: 5082670 (1992-01-01), Gage et al.
patent: 5529774 (1996-06-01), Barba et al.
patent: 5650148 (1997-07-01), Gage et al.
patent: 5683695 (1997-11-01), Shen et al.
patent: 5756312 (1998-05-01), Weiner et al.
patent: 5762926 (1998-06-01), Gage et al.
patent: WO 90/06757 (1990-06-01), None
Deonarain, M., 1998, Exp. Opin. Ther. Patents, vol. 8, No. 1, p. 53-69.*
Eck et ak., 1996, “Goodman & Gilman's The Pharmacological Basis of therapeutics”, Ninth Edition, McGraw-Hill, New York, p. 77-101.*
Gorecki, D., 2001, Expert Opin. Emerging Drugs, vol. 6, No. 2, p. 1870198.*
Castro et al., 2001, Histol. Histopathol., vol. 16, p. 1225-1238.*
Armelin et al., “Pituitary extracts and steroid hormones in the control of 3T3 cell growth”Proc. Natl. Acad. Sci.(1973) 70:2702-6.
Banerji et al., “Expression of a beta-globin gene is enhanced by remote SV40 DNA sequences”Cell(1981) 27:299-308.
Benoist et al., “In vivo sequence requirements of the SV40 early promoter region”Nature(1981) 290:304-10.
Blesch et al., “Ex vivo gene therapy for Alzheimer's disease and spinal cord injury”Clinical Neuroscience(1996) 3:268-274.
Borsani et al., “cDNA sequence of human beta-NGF”Nucleic Acids Res.(1990) 18:4020.
Breathnach et al., “Organization and expression of eucaryotic split genes coding for proteins”Ann. Rev. Biochem.(1981) 50:349-83.
Chen et al., “Calcium phosphate-mediated gene transfer: a highly efficient transfection system for stably transforming cells with plasmid DNA”BioTechniques(1988) 6:632-8.
Chen et al., “High-efficiency transformation of mammalian cells by plasmid DNA”Mol. Cell. Biol.(1987) 7:2745-52.
Chua et al., “Tumor necrosis factor-alpha induces mRNA for collagenase and TIMP in human skin fibroblasts”Connect. Tissue Res.(1990) 25:161-170.
Conner et al., “Distribution of NGF delivered into the rat CNS by either grafted NGF-secreting fibroblasts, intraparenchymal (IP) injections, or IP-infusions”Society for Neuroscience(1997) 23:53 Abstract 29.5.
Corden et al., “Promoter sequences of eukaryotic protein-coding genes.”Science(1980) 209:1406-14.
DePamphilis et al., “Microinjecting DNA into mouse ova to study DNA replication and gene expression and to produce transgenic animals”BioTechniques(1988) 6:662-80.
de Wet et al., “The mRNAs for the pro-alpha 1(I) and pro-alpha 2(I) chains of type I procollagen are translated at the same rate in normal human fibroblasts and in fibroblasts from two variants of osteogenesis imperfecta with altered steady state ratios of the two mRNAs”J. Biol. Chem.(1983) 258:14385-9.
Elias et al., “Regulation of human lung fibroblast collagen production by recombinant interleukin-1, tumor necrosis factor, and interferon-gamma”Ann. N.Y. Acad. Sci.(1990) 580:233-244.
Felgner et al., “Cationic liposome mediated transfection”Proc. West. Pharmacol. Soc.(1989) 32:115-21.
Felgner et al., “Cationic liposome mediated transfection”Focus. (1989) 11:21-25.
Felgner et al., “Lipofection: a highly efficient, lipid-mediated DNA-transfection procedure”Proc. Natl. Acad. Sci.(1987) 84:7413-7.
Fraley et al., “New generation liposomes: the engineering of an efficient vehicle for intracellular delivery of nucleic acids”Trends Biochem. Sci.(1981) 6:77-80.
Fromm et al., “Deletion mapping of DNA regions required for SV40 early region promoter function in vivo”J. Mol. Appl. Genet.(1982) 1:457-81.
Gruss et al., “Simian virus 40 tandem repeated sequences as an element of the early promoter”Proc. Natl. Acad. Sci.(1981) 78:943-7.
Hefti et al., “Nerve growth factor and Alzheimer's disease”Ann. Neurol.(1986) 20:275-81.
Higgins et al., “NGF receptor gene expression is decreased in the nucleus basalis in Alzheimer's disease”Exp. Neurol.(1989) 106:222-36.
Horellou et al., “Adenovirus-mediated gene transfer to the central nervous system for Parkinson's Disease”Experimental Neurobiology(1997) 144:131-8.
Jolly et al., “Elements in the long terminal repeat of murine retroviruses enhance stable transformation by thymidine kinase gene”Nucleic Acids Res.(1983) 11:1855-1872.
Kobayashi et al., “Morphometric study on the CH$ of the nucleus basalis of Meynert in Alzheimer's disease”Mol. Chem. Neuropathol.(1991) 15:193-206.
Kojima, et al., “Adenovirus-Mediated transduction with human glial cell line-derived neurotrophic factor gene prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopamine depletion in str
Chen Shin-Lin
Foley & Lardner LLP
Regents of the University of California
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