Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1997-03-21
2002-06-18
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S021800, C530S324000, C530S350000
Reexamination Certificate
active
06407060
ABSTRACT:
FIELD OF THE INVENTION
The present invention generally relates to methods and compositions for the treatment of mammals, including humans, following an ischemic or traumatic injury to the central nervous system.
BACKGROUND OF THE INVENTION
Numerous proteins have now been identified and characterized as morphogenetic or growth factors, regulating cell proliferation and/or differentiation of tissues in vertebrates, including mammals. Typically these growth factors exert their effects on specific subsets of cells and/or tissues. Thus, for example, epidermal growth factors, nerve growth factors, fibroblast growth factors, various hormones, and many other proteins inducing or inhibiting cell proliferation or differentiation have been identified and shown to affect some subset of cells or tissues.
Neurotrophic factors are polypeptides that are required for the development of the nervous system. The first neurotrophic factor discovered, nerve growth factor (NGF), is now known to be a part of a large family of growth factors, which also includes BDNF, NT3, and NT4/NT5. The dimeric proteins defined in PCT Publication No. WO 94/03200 as morphogens constitute another family of proteins believed to play an important role in neural development (Jones, et al. (1991)
Development
111: 531-542; Ozkaynak, et al. (1992)
J. Biol. Chem
. 267: 25220-25227; Lein, et al. (1995)
Neuron
15: 597-605).
These proteins, referred to herein as “morphogenic proteins” or “morphogens,” are competent to act as true tissue morphogens, able, on their own, to induce the proliferation and differentiation of progenitor cells into functional mammalian body tissue. The proteins include members of the family of bone morphogenetic proteins (BMPs) which were initially identified by their ability to induce ectopic, endochondral bone morphogenesis.
Morphogens generally are classified in the art as a subgroup of the TGF-&bgr; superfamily of growth factors (Hogan (1996)
Genes
&
Development
10: 1580-1594). Members of the morphogen family of proteins include the mammalian osteogenic protein-1 (OP-1, also known as BMP-7, and the Drosophila homolog 60A), osteogenic protein-2 (OP-2, also known as BMP-8), osteogenic protein-3 (OP-3), BMP-2 (also known as BMP-2A or CBMP-2A, and the Drosophila homolog DPP), BMP-3, BMP-4 (also known as BMP-2B or CBMP-2B), BMP-5, BMP-6 and its murine homolog Vgr-1, BMP-9, BMP-10, BMP-11, BMP-12, GDF-3 (also known as Vgr2), GDF-8, GDF-9, GDF-10, GDF-11, GDF-12, BMP-13, BMP-14, BMP-15, GDF-5 (also known as CDMP-1 or MP52), GDF-6 (also known as CDMP-2), GDF-7 (also known as CDMP-3), the Xenopus homolog Vgl and NODAL, UNIVIN, SCREW, ADMP, and NEURAL. The members of this family encode secreted polypeptide chains sharing common structural features, including processing from a precursor “pro-form” to yield a mature polypeptide chain competent to dimerize, and containing a carboxy terminal active domain of approximately 97-106 amino acids. All members share a conserved pattern of cysteines in this domain and the active form of these proteins can be either a disulfide-bonded homodimer of a single family member, or a heterodimer of two different members (see, e.g., Massague (1990)
Annu. Rev. Cell Biol
. 6: 597; Sampath, et al. (1990)
J. Biol. Chem
. 265: 13198). See also, U.S. Pat. No. 5,011,691; U.S. Pat. No. 5,266,683, Ozkaynak et al. (1990)
EMBO J
. 9: 2085-2093, Wharton et al. (1991)
PNAS
88: 9214-9218), (Ozkaynak (1992)
J. Biol. Chem
. 267: 25220-25227 and U.S. Pat. No. 5,266,683); (Celeste etal. (1991)
PNAS
87: 9843-9847); (Lyons et al. (1989)
PNAS
86: 4554-4558). These disclosures describe the amino acid and DNA sequences, as well as the chemical and physical characteristics of these morphogenic proteins. See also Wozney et al. (1988)
Science
242: 1528-1534); BMP-9 (WO 93/00432, published Jan. 7, 1993); DPP (Padgett et al. (1987)
Nature
325: 81-84; and Vg-1 (Weeks (1987) Cell 51: 861-867).
Morphogens are expressed naturally in a variety of tissues during development, including those of the developing nervous system (Ozkaynak, et al. (1990)
EMBO J
. 9: 2085-2093; Ozkaynak, et al. (1991)
Biochem. Biophys. Res. Commun
. 179:116-123; Ozkaynak, et al. (1992) supra).
Vascular diseases of the nervous system rank first in frequency amongst all the neurologic diseases; they constitute about fifty percent of all neurologic hospital admissions to adult wards. The cardinal feature of cerebrovascular disease is the stroke, a term that connotes the sudden and dramatic development of a focal neurologic deficit. Obstruction of a nutrient artery supplying a locus of the central nervous system by, for example, a thrombus or an embolus or a failure of the systemic circulation and hypotension, if severe and prolonged enough, can deprive brain tissue of blood and oxygen, leading to disruption of physiologic function, subsequent death of neurons, and necrosis (infarction) of the affected locus. In hemorrhagic infarction, an extravasation of blood occurs into the brain tissue, the subarachnoid space, or both. Damage results from physical disruption of the region directly involved and pressure of the mass of blood on the surrounding tissue.
The neurologic deficit in a stroke reflects both the location and the size of the infarct or hemorrhage in the brain. Hemiplegia is the classic sign of vascular disease and occurs with strokes involving the cerebral hemisphere or the brainstem. However, depending on its location, a stroke may also give rise to many other manifestations accompanying or independent of hemiplegia, including numbness, sensory deficit, dysphasia, blindness, diplopia, dizziness, and dysarthria.
Patients who suffer a “stroke,” or any other form of cerebral ischemic or traumatic injury, usually recover partially, but often remain mildly to severely debilitated. For example, total infarction of the middle cerebral artery in a human results in a contralateral hemiplegia, hemianesthesia, homonymous hemianopia, global or total sensorimotor aphasia (left hemisphere), and apractagnosia (right hemisphere). Once established, the motor, sensory, and language deficits usually remain static or very little improved after the passage of months or even years. Seldom can the patient ever again communicate effectively. Currently, aside from physical therapy, there is no treatment that reliably improves the prognosis of a patient who has suffered a stroke or any similar injury of the central nervous system.
SUMMARY OF THE INVENTION
The present invention is directed to methods and compositions for treatment of mammals afflicted with an ischemic or traumatic injury of the central nervous system. In particular, the invention provides treatments for mammals in whom central nervous system tissue has been damaged or lost due to stroke or a similar disruption in blood flow, or due to infliction of physical (e.g., mechanical) trauma affecting the central nervous system. The methods and compositions provided herein capitalize upon the discovery that administration of a morphogen to such a mammal provides significant improvement in central nervous system function, even when administered after central nervous system tissue has been damaged. The methods involve the administration of dimeric proteins defined as morphogens, inducers of these morphogens, or agonists of the corresponding morphogen receptors, or implantation of cells stimulated by exposure to the morphogens.
Accordingly, the invention features a method for treating a mammal who has suffered an injury to the central nervous system, such as a stroke or a traumatic injury. The method involves administering an effective dose of morphogen to the mammal at least six hours after the onset of the injury; for example, twelve, twenty-four, or forty-eight hours or even longer following the onset of injury.
The treatment regimen according to the invention is carried out in terms of administration mode, timing of the administration, and dosage, so that the functional recovery from impairment of the central nervous system is enhanced. The compositions of the present inven
Charette Marc F.
Finklestein Seth P.
Curis, Inc.
Delacroix-Muirheid C.
Henley III Raymond
Ropes & Gray
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