Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1997-09-08
2001-07-31
Weber, Jon P. (Department: 1651)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S002600
Reexamination Certificate
active
06268340
ABSTRACT:
The present invention concerns a novel method for the regeneration of oligodendrocytes, in particular, of human oligodendrocytes, and for the treatment of diseases in which a demyelination of nerve fibers occurs, a method of manufacturing a therapeutic agent, as well as the use of human &bgr; nerve growth factor (NGF) for said therapeutic use.
The covering of nerve fibers in the central nervous system (CNS) with myelin is essential for the function of neuronal signal transmission. The myelin sheath is formed by oligodendrocytes (OL), the fibers of which wrap around the axon of a nerve cell. Demyelinating diseases such as multiple sclerosis in which the myelin sheath of the axon is damaged or destroyed also lead to impairments of the OL. However, the OL remains capable of regenerating the myelin sheaths. Therefore, the identification and characterization of factors which are responsible for increased regeneration of OL is very important for the molecular understanding of demyelination diseases, such as multiple sclerosis (MS), and for the development of therapeutic agents.
It is known from PCT/EP92/01173 (17) that the regeneration of oligodendrocytes is improved when they are treated with NGF or active fragments of NGF.
NGF is a neurotrophic factor which is well characterized. Its gene is described in Ullrich et al. (1993) (1) and EP-B 0 121 338 (U.S. Pat. No. 5,169,762) (13). The recombinant production of NGF from
E.coli
is described in EP-A 0 544 293 (15), EP-A 0 450 386 (U.S. Pat. No. 5,235,043) (14), EP-A 0 370 171 (16) and U.S. Ser. No. 08/266610 (18).
NGF has potent and beneficial effects on cholinergic neurons after axotomy (see, for example, Hoffman et al. (1990) (2)). NGF infusions stimulate the regeneration of transsected cholinergic neurons (Gage (1988) (3), Tuszynski et al. (1990) (4)). It is further known that infusions of NGF stimulate the expression of choline acetyltransferase (ChAT) (Hefti et al. (1984) (5) and p75NGF receptor mRNA (Gage et al. (1989) (6)).
For the therapeutic application, NGF is infused for a period of several weeks. Olson et al. (1991) (11) describes an infusion of NGF through an intraventricular cannula for 23 days with a total dose of 3.3 mg (corresponding to approximately 140 &mgr;g/24 hr) for the treatment of Parkinson's patients after having received fetal dopaminergic grafts. It is also known to deliver NGF therapeutically in Alzheimer's disease via a programmable pump planted subcutaneously into the abdominal wall and connected by a subcutaneous catheter to the intraventricular catheter. To the patient a total of 6.6 mg of NGF was delivered during three months at a rate of 15 &mgr;l/hr (corresponding to approximately 75 &mgr;g/24 hr (Olson et al. (1992) (12))).
SUMMARY OF THE INVENTION
It was surprisingly found that for the regeneration of oligodendrocytes, i.e. in MS, an interval application leads to an improved and accelerated remyelination of damaged nerve fibers as compared to continuous application of the therapeutic agent.
The invention concerns a method of preparing a therapeutic agent for the treatment of multiple sclerosis, the method being characterized in that human &bgr; nerve growth factor (NGF) is brought into a pharmaceutically acceptable formulation for administering in a dose between 0.05 &mgr;g and 5 &mgr;g/kg body weight in 1 to 10 bolus injections at an interval of 1 to 21 days, preferably 1 to 12 days.
According to the invention, NGF is administered in a dose between 0.05 &mgr;g and 5 &mgr;g/kg, 3.5 to 350 &mgr;g, preferably 3.5 to 210 &mgr;g per injection, at an interval of 1 to 21 days. Preferably, the dose is applied in 1 to 10 injections.
In a preferred embodiment of the invention, it is preferred to use 0.01 &mgr;g to 3 &mgr;g/kg, and more preferably 0.1 &mgr;g to 1 &mgr;g/kg.
It is preferred to administer NGF intrathecally, into the cerebrospinal fluid space of the ventricle or spinal cord, preferably of the lateral ventricle or the lumbar spinal cord.
DETAILED DESCRIPTION OF THE INVENTION
The term “NGF” means &bgr;-unit of human NGF. &bgr;-NGF has an amino acid sequence of 118 amino acids and is present as a dimer in solution. The amino acid and DNA sequence is described in Ullrich et al. (1993) (1).
The pharmaceutical compositions which are used according to the invention and contain &bgr;-NGF may be administered in any sterile biocompatible pharmaceutical carrier, including, but not limited to, saline, buffered saline or dextrose solution, preferably in an acidic solution having a pH of about 4 to 5, preferably in an acetate buffer. The amount of NGF protein which will be effective in the treatment of MS is in a dose between 0.05 &mgr;g and 5 &mgr;g/kg body weight at an interval of 1 to 21 days, preferably in 1 to 10 injections. It is further preferred to use 3.5 to 350 &mgr;g/injection.
Methods of introduction include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, oral, intrapeulmonal and intranasal administration. In addition, it may be desirable to introduce the pharmaceutical composition of the invention into the central nervous system by any suitable route, including intrathecal, e.g. intraventricular injection. Intraventricular injection may be facilitated by an intraventricular catheter, for example attached to a reservoir, such as an implantable port catheter system, such as the Periplant® filtrosafe (B. Braun GmbH, Spangenberg, DE).
Furthermore, it may be desirable to administer the pharmaceutical compositions, which are used according to the invention, locally to the area in need of treatment. This may be achieved by, for example, and not by way of limitation, injection by means of a catheter or by means of an implant, said implant being of a porous, non-porous or gelatinous material, including membranes, such as sialastic membranes or fibers. NGF is preferably administered during the relapse period. If high doses are used, only a few or even one bolus application is sufficient.
REFERENCES:
patent: 5885584 (1999-03-01), Althaus et al.
patent: 93/03140 (1993-02-01), None
Unger et al., Poster presented at theAnnual Meeting of the Society for Neuroscience, San Diego, California, Nov. 11-16, 1995, “Time course of regeneration in the adult pig brain following lysolecithin-induced demyelination”.
Althaus et al.,Neurosci. Lett.135 (2) (1992) pp. 219-223, “Nerve growth factor induces proliferation and enhances fiber regeneration in oligodendrocytes isolated from adult pig brain”.
Olson et al.,Arch Neurol.48 (4) (1991) pp. 373-387, “Intraputaminal infusion of nerve growth factor to support adrenal medullary autografts in Parkinson's disease one-year follow-up of first clinical trial”.
Olson et al.,J. Neural. Transm. Parkinson's Dis. Dementia Sect.4 (1) (1992) pp. 79-96, “Nerve growth factor affects carbon-11 nicotine blinding blood flow eeg and verbal episodic memory in an Alzheimer patient”.
Engel et al. (1994) NeuroReports, 5(4), “NGF Increases [Ca2+]iin Regenerating Oligodendroglial Cells”, pp. 397-400.
Bartke Ilse
Naujoks Kurt
Schmidt Yorn
Unger Jurgen
Arent Fox Kintner & Plotkin & Kahn, PLLC
Roche Diagnostics GmbH
Weber Jon P.
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