Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1997-03-21
2001-04-10
Jones, Dwayne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C530S399000
Reexamination Certificate
active
06214796
ABSTRACT:
The field of the invention is the treatment of ischemic injury of the central nervous system.
BACKGROUND OF THE INVENTION
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 brain-derived neurotrophic factor (BDNF) and the neurotrophins (NT3 and NT4/NT5). Fibroblast growth factors (FGFs) constitute another large family of polypeptide growth factors that induce mitogenic, chemotactic, and angiogenic activity in a wide variety of cells, including neurons (Thomas,
FASEB J.
1:434-440, 1987; Burgess et al.,
Ann. Rev. Biochem.
58:575-606, 1989; Moscatelli et al., U.S. Pat. No. 4,994,559). While the role of polypeptide growth factors in the developing animal has become increasingly evident, their role in the mature animal, particularly in the nervous system, is much less clear.
Injury or death of neurons in a mature animal produces motor and/or cognitive deficits that are often permanent. Patients who suffer a “stroke,” or any other form of cerebral ischemic episode, usually recover partially, but often remain mildly to severely debilitated. Currently, aside from physical therapy, there is no treatment that reliably improves the prognosis of a patient who has suffered a cerebral ischemic episode.
SUMMARY OF THE INVENTION
We have discovered that administration of a polypeptide growth factor provides significant benefits following a cerebral ischemic episode, even when administration occurs a significant amount of time following that episode. Furthermore, functional recovery occurs without a reduction in the size of the infarct (i.e., the necrotic tissue that is produced by ischemia).
Accordingly, the invention features a method for treating a patient who has suffered an injury to the central nervous system, such as an ischemic episode or a traumatic injury, by administering to the patient a polypeptide growth factor, wherein administration occurs more than six hours after the onset of the injury; administration can beneficially occur even later, i.e., twelve, twenty-four, forty-eight, or more hours following the ischemic episode.
The polypeptide growth factor administered may be: a member of the fibroblast growth factor (FGF) family, such as basic FGF (bFGF), acidic FGF (aFGF), the hst/Kfgf gene product, FGF-5, or int-2; a member of the neurotrophin family, such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), or neurotrophin 4/5 (NT4/5); an insulin-like growth factor (IGF), such as IGF-1, or IGF-2; ciliary neurotrophic growth factor (CNTF); leukemia inhibitory factor (LIF); oncostatin M; or an interleukin.
Also included in the invention are “functional polypeptide growth factors,” which possess one or more of the biological functions or activities of the polypeptide growth factors described herein. These functions or activities are described in detail below and concern, primarily, enhancement of recovery following an ischemic event within the central nervous system. Accordingly, alternate molecular forms of polypeptide growth factors are within the scope of the invention. For example, forms of bFGF have been observed with molecular weights of 17.8, 22.5, 23.1, and 24.2 kDa. The higher molecular weight forms being colinear N-terminal extensions of the 17.8 kDa bFGF (Florkiewicz et al.,
Proc. Natl. Acad. Sci. USA
86:3978-3981, 1989).
Alternatively, polypeptide growth factors useful in the invention can consist of active fragments of the factors. By “active fragment,” as used herein in reference to polypeptide growth factors, is meant any portion of a polypeptide that is capable of invoking the same activity as the full-length polypeptide. The active fragment will produce at least 40%, preferably at least 50%, more preferably at least 70%, and most preferably at least 90% (including up to 100%) of the activity of the full-length polypeptide. The activity of any given fragment can be readily determined in any number of ways. For example, a fragment of bFGF that, when administered according to the methods of the invention described herein, is shown to produce performance in functional tests that is comparable to the performance that is produced by administration of the full-length bFGF polypeptide, would be an “active fragment” of bFGF. It is well within the abilities of skilled artisans to determine whether a polypeptide growth factor, regardless of size, retains the functional activity of a full length, wild type polypeptide growth factor.
As used herein, both “protein” and “polypeptide” mean any chain of amino acid residues, regardless of length or post-translational modification (e.g., glycosylation or phosphorylation). The polypeptide growth factors useful in the invention are referred to as “substantially pure,” meaning that a composition containing the polypeptide is at least 60% by weight (dry weight) the polypeptide of interest, e.g., a bFGF polypeptide. Preferably, the polypeptide composition is at least 75%, more preferably at least 90%, and most preferably at least 99%, by weight, the polypeptide of interest. Purity can be measured by any appropriate standard method, e.g., column chromatography, polyacrylamide gel electrophoresis, or HPLC analysis.
Furthermore, the nomenclature in the field of polypeptide growth factors is complex, primarily because many factors have been isolated independently by different groups of researchers and, historically, named for the type of tissue that was used as an assay in the process of purifying the factor. Basic FGF has been referred to in scientific publications by at least 23 different names. These include leukemic growth factor, macrophage growth factor, embryonic kidney-derived angiogenesis factor 2, prostatic growth factor, astroglial growth factor 2, endothelial growth factor, tumor angiogenesis factor, hepatoma growth factor, chondrosarcoma growth factor, cartilage-derived growth factor 1, eye-derived growth factor 1, heparin-binding growth factors class II, myogenic growth factor, human placenta purified factor, uterine-derived growth factor, embryonic carcinoma-derived growth factor, human pituitary growth factor, pituitary-derived chondrocyte growth factor, adipocyte growth factor, prostatic osteoblastic factor, and mammary tumor-derived growth factor. Thus, any factor referred to by one of the aforementioned names is considered within the scope of the invention.
The polypeptide growth factors useful in the invention can be naturally occurring, synthetic, or recombinant molecules consisting of a hybrid or chimeric polypeptide with one portion, for example, being bFGF, and a second portion being a distinct polypeptide. These factors can be purified from a biological sample, chemically synthesized, or produced recombinantly by standard techniques (see e.g., Ausubel et al.,
Current Protocols in Molecular Biology
, New York, John Wiley and Sons, 1993; Pouwels et al.,
Cloning Vectors: A Laboratory Manual,
1985, Supp. 1987).
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 of the patient from the adverse consequences of the central nervous system injury is improved; i.e., the patient's motor skills (e.g., posture, balance, grasp, or gait), cognitive skills, speech, and/or sensory perception (including visual ability, taste, olfaction, and proprioception) improve as a result of polypeptide growth factor administration according to the invention.
Administration of polypeptide growth factors according to the invention can be carried out by any known route of administration, including intravenously, orally, or intracerebrally (e.g., intraventricularly, intrathecally, or intracisternally); intracisternal administration can be carried out, e.g., using 0.1 to 100 &mgr;g/kg/injection and administering a single injection or a series of injections. For example, intracistern
Delacroix-Muirhead C.
Fish & Richardson P.C.
Jones Dwayne C.
The General Hospital Corporation
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