Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1998-10-29
2001-04-24
Russel, Jeffrey E. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S021800, C530S399000
Reexamination Certificate
active
06221842
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to improvements in treating muscle disorders and related conditions using insulin-like growth factor I.
BACKGROUND OF THE INVENTION
insulin-like growth factor I (IGF-I) is a peptide present in the plasma and other body fluids. In its mature processed form it comprises 70 amino acids and can stimulate growth of a wide range of cell types. Human IGF-I have been cloned and its cDNA sequence can be found in Jansen et al, Nature, 1993 (reference 11 below). The cDNA sequence encodes a precursor (also known as the D-chain), a mature 70 amino acid comprising the B, C and A regions respectively, and a C-terminal region which is termed the E-peptide. Recently, it has been found that the E-peptide can exist in different isoforms. This arises as a result of alternative splicing at the mRNA level. Chew et al report the existence of three alternatively spliced T-terminal regions of human IGF-I. One of the isoforms produced is as a result of splicing between exons 4, 5 and 6 of the gene and this predicts a prepro-IGF-I molecule of 158 amino acids including a C-terminal peptide, the Ec peptide of 24 amino acids in length. This Ec peptide appears to correspond to the Eb peptide found in rat IGF-I.
IGF-I has been proposed for use of a number of disorders relating to muscle atrophy and related conditions. For example, WO92/11865 proposes the use of human IGF-I for the prevention or treatment of cardiac disorders and for the promotion of cardiac muscle protein synthesis, for prevention or treatment of cardiomyophthies, acute heart failure or acute insult including myocarditis or myocardial infarction and for improving cardiac output by increasing heart/volume. WO95/13290 relates to the use of IGF-I for treating muscular disorders such as muscular dystrophy and related progressive skeletal muscle weakness and wasting.
W093/09236 teaches methods of gene therapy using myogenic vector systems comprising promoters suitable for use in muscle cells. Such vectors may be introduced into a human patient for the treatment of muscle atrophy in ageing humans, muscle atrophy induced by spinal cord injuries or neuromuscular diseases.
A difficulty with the use of IGF-I is that this peptide is responsible for a wide range of effects within the human body. Although IGF-I is produced in muscle cells it is also produced in the liver from where it circulates and is involved in regulating metabolism. Administration of IGF-I may thus induce side-effects including hypoglycaemia.
De Vol et al (1990), Am. J. Physiol. 259, E89-E95) report that IGF-I expression is elevated during work-induced skeletal muscle growth.
SUMMARY OF THE INVENTION
We have investigated the production of IGF-I in skeletal muscles and have surprisingly found that whereas resting muscles normally produce the liver IGF-I isoform including the Ea peptide, muscle cells induced to undergo rapid hypertrophy using active stretch rapidly up-regulate the production of a different IGF-I isoform. We have thus found that the IGF-I Ec isoform in humans, corresponding to the IGF-I Eb isoform in rats and rabbits, may play an important role in targeting the action of IGF-I to muscle cells. Thus, treatment of muscular disorders such as those mentioned above may be improved by the use of the human Ec isoform or the Ec peptide of human IGF-I.
Accordingly, the present invention provides a human IGF-I polypeptide or functional derivative thereof characterised by the presence of the Ec peptide for use in a method of treatment or therapy of the human or animal body. The invention also provides pharmaceutical compositions comprising such polypeptides.
The invention further provides a method for the treatment of muscular disorders of the human body which comprises administering to a patient in need of such treatment an effective amount of IGF-I or a functional derivative thereof which is characterised by the presence of Ec peptide.
REFERENCES:
patent: 0 229 750 (1987-07-01), None
patent: WO 92/11865 (1992-07-01), None
patent: WO 93/0923 (1993-05-01), None
patent: WO 95/13290 (1995-05-01), None
Chew et al, Endocrinology vol. 136, No. 5 (1995) pp 1939-1944 An Alternatively Spliced Human etc.
Yang et al J. of Muscle Research and Cell Motility 17, 487-495 (1996) Cloning and Characterization etc.
Goldspink et al Amer.J. of Physiology (Feb. 1995)p. vol. 268, No. 2 Muscle Growth in response to mechanical stimuli.
Edwall et al Endocrinology, vol. 124, No. 2 (1989) p. 820-825 Induction of Insulin-Like Growth Factor etc.
DeVol et al Amer. J. of Physiology(Jul. 1990)vol. 259, No. 1 E89-E95 Activation of insulin-like growth factor etc.
Lowe et al Molecular Endocrinology vol. 2, No. 6,(Jun. 1988) 528-535 Distribution and Regulation of Rat Insulin etc.
Han et al Science, vol. 236, 1(Apr. 1987)Cellular Localization of Somatomedin (Insulin-Like Growth Factor) etc.
Jansen et al Nature 306, 609-611, (1983)Sequence of cDNA encoding human insulin-like growth factor I etc.
Caroni et al J. of Neuroscience,(May 1994)14(5): 3378-3388 Signalling by Insulin-Like Growth Factors in etc.
Goldspink et al Amer J. of Physiology 262, R356-R363, (1992)Gene expression in skeletal muscle in etc.
Goldspink et al European J. of Physiology(1986)407:333-340 The effect of hypokinesia and hypodynamia etc.
Valenzuela et al Neuron, vol. 15, 573-584 (Sep. 1995)Receptor Tyrosine Kinase Specific for the Skeletal etc.
Goldspink et al J. Physiology(1996), 162P-163P, Local Growth Regulation is Associated with an Isoform etc.
Nixon & Vanderhye P.C.
Russel Jeffrey E.
University College London
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