Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Hormones – e.g. – prolactin – thymosin – growth factors – etc.
Patent
1996-06-28
1999-08-17
Allen, Marianne P.
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Hormones, e.g., prolactin, thymosin, growth factors, etc.
530350, 530351, C12N 1518, C07K 14475, C07K 14535, C07K 1452
Patent
active
059395346
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to a novel mutant of a human ciliary neurotrophic factor (hereinbelow abbreviated as human CNTF) and a protein having a four-helix bundle structure similar to that of human CNTF, which are expected to be useful for the treatment of neuropathic diseases. The present invention also relates to a DNA containing the nucleotide sequence encoding the mutant and an expression vector carrying the DNA as well as a transformant transformed with the expression vector.
BACKGROUND ART
Human CNTF was discovered by Silvio Varon et al. in 1979 to be a factor for promoting the survival of ciliary ganglions which are parasympathetic nerves (Brain Res., 173, 29-45 (1979)). Subsequently, the purification and cloning of human CNTF were reported in G. Barbin et al., J. Neurochem., 43, 1468-1478 (1984); L. F. Lin et al., Science, 246, 1023 (1989); P. Masiakowski et al., J. Neurochem., 57, 1003 (1991); A. Negro et al., Dur. J. Biochem, 201, 289 (1991); J. R. McDonald et al., Biochim. Biophys. Acta, 70, 1090 (1991); WO 90/7341 and WO 91/4316.
In connection with the pharmacological activities of human CNTF in vitro, there are the following reports on the survival promoting activity of human CNTF on hippocampal and septal GABA-mediated neurons (N. Y. IP et al., N. Neursci., 11, 3124-3134 (1991)); on optic neurons (H. D. Hoffman, J. Neurochem., 51, 109-113 (1988)); on sensory neurons (G. Barbin et al., J. Neurochem., 43, 1468-1478 (1984)); on parasympathetic neurons (Y. Arakawa et al., J. Neursci., 10, 3507-3515 (1990)) and on motor neurons (M. Sendtner et al. J. Cell Sciences supple., 15, 103-109 (1991)); and on the differentiation activity of human CNTF into cholinergic neurons (S. Saadat et al., J. Cell Biol., 108, 1807-1816 (1989) and U. Ernsberger et al., Neuron, 2, 1275-1284 (1989)) and into type 2A astrocytes (D. J. Anderson et al., TINS, 12, 83 (1989)); the in vivo activities are reported on the survival promoting effect on septal cholinergic neurons in a fimbria-fornix trunsection model (T. Hagg et al., Neuron, 8, 145 (1992))1D on the survival promoting activity of human CNTF on motor neurons in an axotomy model (M. Sendtner et al., Nature, 345, 440-441 (1990)); on the survival promoting activity of human CNTF on motor neurons in mice with genetic motor disorders (M. Sendtner et al. in Nature, 358, 502-503 (1992)); on the protecting effect of human CNTF for substantia nigra dopaminergic neurons in a substantia nigra-striatun trunsection model (T. Hogg & S. Varon, Proc. Natl. Acad. Sci., USA, 90, 6315-6319 (1993)); on the protecting effect for a photoreceptor (M. M. LaVail et al., Proc. Natl. Acad. Sci., USA, 89, 11249-11253 (1992)); on the protecting effect for optic neurons (K. Unoki & M. M. LaVail in Investigative Ophthalmology & Visual Sciences 35, 907-915 (1994)); and so on.
As reported above human CNTF acts on neurons to exert the activities of promoting the survival of neurons, accelerating the neurite outgrowth of neurons and stimulating the synthesis of neurotransmitters. Human CNTF is thus expected to be useful for the treatment of trauma-induced nervous disorders, diseases caused by atrophy or denaturation of neurons including Alzheimer's disease, cerebrovascular dementia and amyotrophic lateral sclerosis (J. E. Springer, DN & P, 4, 394 (1991) R. M. Lindsay, Neurobiol. of Aging, 15, 249-251 (1994) and R. M. Lindsay, TINS, 17, 182 (1994)).
It is also reported that human CNTF effectively displays, in combination with brain-derived neurotrophic factor (BDNF) a protecting activity on nervous disorders in a neurodegenerative animal model (Wobbler mice) (H. Mitsumoto et al., Science, 265, 1107-1110 (1994)). It is suggested that human CNTF will be an effective drug for the treatment of nervous disorders, not only by human CNTF alone but also in combination with other neurotrophic factors (R. Nishi, Sciences, 265, 1052-1053 (1994)).
However, in clinical trials of wild type human CNTF currently used in USA for the treatment of amyotrophic lateral sclerosis, a considerably lar
REFERENCES:
patent: 5349056 (1994-09-01), Panayotatos
Robinson, R.C. et al., Cell, 77(7): 1101-1116, 1994.
Bazan, J.F. et al., Neuron, 7(2): 197-208, 1991.
Brakenhoff, J.P.J. et al., J. Biol. Chem., 269 (1): 86-93, 1994.
Sprang, S.R. et al., Curr. Opin. Struct. Biol., 3(6): 815-27, 1993.
Panayotatos, N. et al., J. Biol. Chem., 268(25): 19000-19003, 1993.
Boulay, J.L. et al., Current Biology, 3(9): 573-81, 1993.
Inoue Makoto
Ishige Yoko
Ito Akira
Kikuchi Kaoru
Kimura Toru
Allen Marianne P.
Sumitomo Pharmaceuticals Company Limited
LandOfFree
Factors mutated in the D1 cap region does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Factors mutated in the D1 cap region, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Factors mutated in the D1 cap region will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-315829