Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1994-05-02
2001-03-20
Kunz, Gary L. (Department: 1646)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S012200
Reexamination Certificate
active
06204240
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to methods and pharmaceutical compositions for the treatment or prevention of central nervous system (CNS) damage and relates particularly to methods of treatment comprising increasing the concentration of transforming growth factor beta 1 (TGF-&bgr;1) and/or analogues thereof in the central nervous system of the patient to treat an injury or disease that causes damage to cells of the CNS.
BACKGROUND OF THE INVENTION
After asphyxial, traumatic, toxic, infectious, degenerative, metabolic, ischemic or hypoxic insults to the central nervous system (CNS) of man a certain degree of neural damage may result. For example, such neural damage can occur in cases of perinatal asphyxia associated with intrapartum fetal distress such as following abruption, cord occlusion or associated with intrauterine growth retardation; perinatal asphyxia associated with failure of adequate resuscitation or apnea; severe neural insults associated with near miss drowning, carbon monoxide inhalation, ammonia of other gaseous intoxication, cardiac arrest, collapse, coma, meningitis, hypoglycemia, or status epilepticus; episodes of cerebral asphyxia associated with coronary bypass surgery; cerebral anoxia or ischemia associated with stroke, hypotensive episodes, hypertensive crises; cerebral trauma; or cerebral degenerative diseases such as Alzheimers disease and multiple sclerosis.
Such neural damage can involve several different cell types of the CNS. For example, periventricular leucomalacia, a lesion which affects the periventricular oligodendrocytes is generally considered to be a consequence of hypoxicischemic injury to the developing preterm brain. Bejar, et al.,
Am. J. Obstet. Gynecol.,
159:357-363 (1988); Sinha, et al.,
Arch. Dis. Child.,
65:1017-1020 (1990); Young, et al.,
Ann. Neurol.,
12:445-448 (1982). Further cholinergic neuronal cell bodies are absent from most regions of the cortex in primates (Mesulam, et al.,
Neurosci.,
12:669-686 (1984)) and rats (Brownstein, et al., in
Handbook of Chemical Neuroanatomy, Classical Transmitters in the CNS
, pp. 23-53 (Elsevier, 1984)). Damage to the cerebral cortex by trauma, asphyxia, ischemia, toxins or infection is frequent and may cause sensory, motor or cognitive deficits. Glial cells which are non-neuronal cells in the CNS are necessary for normal CNS function. Infarcts are a principle component of hypoxic-ischemia induced injury and loss of glial cells is an essential component of infarction. Multiple sclerosis is associated with loss of myelin and oligodendrocytes, similarly Parkinson's disease is associated with loss of dopaminergic neurons.
Several growth factors have been reported to be induced after transient hypoxic-ischemia in the brain. After postasphyxial seizures, the proto-oncogene c-fos is induced in surviving neurons and in glial cells from infarcted regions. Gunn, et al.,
Brain Res.,
S31:105-116 (1991). Nerve growth factor (NGF) synthesis is increased after hypoxia or seizures in the hippocampus and cerebral cortex. Lorez, et al.,
Neurosci. Lett.,
98:339-344 (1989); Gall, et al.,
Science,
245:758-761 (1989). However, little is known of the role of cytokines in brain injury. Glial cells have been shown to produce a number of cytyokines including interleukin 3 (lL-3) and interleukin 6 (lL-6). Interleukin 1 (lL-1) has been reported to be elevated in cerebrospinal fluid after head injury in humans. McClain, et al.,
J. Lab. Clin. Med.,
110:48-54 (1987).
Transforming growth factor beta (TGF-&bgr;) is another example of a cytokine and is a multifunctional polypeptide implicated in the regulation of cellular or tissue response to injury or stress. For a general review of TGF-&bgr; and its actions, see Sporn, et al.,
Science,
233:532-534 (1986); Sporn et al.,
J. Cell Biol.,
105:1039-1045 (1987); Sporn, et al.,
Nature,
3232:217-219 (1988); and Sporn, et al, in
Peptide Growth Factors and Their Receptors l
, pp.419-472 (Springer-Verlag, 1990). TGF-&bgr; is found in various mammalian tissues, such as bone, platelets, and placenta, and methods for purifying the polypeptide from such natural sources, as well as for producing it in recombinant cell culture, have been described. See, for example, Assoian, et al.,
J. Biol. Chem.,
258:7155-7160 (1983); Frolik, et al.,
Proc. Nat. Acad. Sci.,
80:3676-3680 (1983); Heimark, et al.,
Science,
233:1078-1080 (1986); Sporn, et al., U.S. Pat. No. 5,104,977; Derynck, et al.,
Nature,
316:701-705 (1985); Derynck, et al., U.S. Pat. No. 4,886,747.
There are several molecular forms of TGF-&bgr;, including those forms which are commonly referred to as TGF-&bgr;1 (Derynck, et al.,
Nature,
316:701-705 (1985)), TGF-&bgr;2 (deMartin, et al.,
EMBO J.,
3673-3677 (1987); Madison, et al.,
DNA,
7:1-8 (1988)), TGF-&bgr;3 (Jakowlew, et al.,
Mol. Endocrin.,
2:747-755 (1988); Ten Dijke, et al.,
Proc. Nat. Acad. Sci.,
85:4715-4719 (1988); Derynck, et al.,
EMBO J.,
7:3737-3743 (1988)), TGF-&bgr;4 (Jakowlew, et al.,
Mol. Endocrin.,
2:1186-1195 (1988), and TGF-&bgr;5 (Kondaiah, et al.,
J. Biol. Chem.,
265:1089-1093 (1990).
It is an object of the invention to provide methods and pharmaceutical compositions for treating or preventing CNS injury or damage. The invention is based upon the inventors' successful research into the role and effects of TGF-&bgr; in the CNS.
SUMMARY OF THE INVENTION
Accordingly, in a first aspect the invention consists in a method of treating neural damage suffered after a CNS insult characterized in that it comprises the step of increasing the active concentration(s) of TGF-&bgr;1 and/or analogues of TGF-&bgr;1 (such as other molecular forms of TGF-&bgr;) in the CNS of the patient. Preferably, the concentration of TGF-&bgr;1 in the CNS of the patient is increased.
The term “treat” when used herein refers to the effecting of a reduction in the severity of the CNS damage, by reducing infarction, and loss of glial cells, non-cholinergic neuronal cells, or other neuronal cells, suffered after a CNS insult. It encompasses the minimizing of such damage following a CNS insult.
Preferably, TGF-&bgr;1 and/or analogues thereof are administered to the patient directly. Alternatively, a compound may be administered which upon administration to the patient, increases the active concentration of TGF-&bgr;1 or naturally occurring analogues of TGF-&bgr;1 in the CNS of the patient. For example, positively regulating binding proteins of TGF-&bgr;1, or naturally occurring analogues thereof may be administered.
Preferably, the pharmaceutical compositions described herein are administered in the period from the time of injury to 100 hours after the CNS insult and more preferably 0.5 to 8 hours after the CNS insult.
In one embodiment of the invention, said TGF-&bgr;1 and/or an analogue or analogues thereof is administered by lateral cerebro ventricular injection into the brain of a patient in the inclusive period from the time of the CNS insult to 8 hours thereafter.
In another embodiment, TGF-&bgr;1 and/or an analogue or analogues thereof is administered through a surgically inserted shunt into the cerebro ventricle of a patient in the inclusive period from the time of the CNS insult to 8 hours thereafter.
In yet another embodiment, TGF-&bgr;1 and/or an analogue or analogues thereof is administered peripherally into a patient for passage into the lateral ventricle of the brain in the inclusive period of from the time of the CNS insult to 8 hours thereafter.
Preferably, it is TGF-&bgr;1, itself, that is administered by way of lateral cerebro ventricle injection or by use of the surgically inserted shunt.
Preferably the pharmaceutical compositions are administered according to the pattern of injury or time lapsed after a CNS insult.
Preferably the dosage range administered is from about 0.0001 to 100 &mgr;g of TGF-&bgr;1 or said analogue or said compound that elevates the concentration thereof per 100 grams of body weight.
TGF-&bgr;1 may be used alone or in conjunction with other therapeutic agents, including other growth factors de
Gluckman Peter
Nikolics Karoly
Williams Christopher
Flehr Hohbach Test Albritton & Herbert LLP
Genentech Inc.
Gucker Stephen
Johnston Sean
Kunz Gary L.
LandOfFree
TGF-&bgr;1 to improve neural outcome does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with TGF-&bgr;1 to improve neural outcome, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and TGF-&bgr;1 to improve neural outcome will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2520572