Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1997-11-20
2001-07-10
Borin, Michael (Department: 1631)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C530S224000, C435S091200
Reexamination Certificate
active
06258780
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a method and composition for transporting compounds including pharmaceutical compositions across the Blood-Brain Barrier (BBB).
2. Description of Related Art
The Blood-Brain Barrier (BBB) maintains a homeostatic environment in the central nervous system (CNS). The capillaries that supply the blood to the brain have tight junctions which block passage of most molecules through the capillary endothelial membranes. While the membranes do allow passage of lipid soluble materials, such as heroin and other psychoactive drugs, water soluble materials such as glucose, proteins and amino acids do not pass through the BBB. Mediated transport mechanisms exist to transport glucose and essential amino acids across the BBB. Active transport mechanisms remove molecules which become in excess, such as potassium, from the brain. For a general review see Goldstein and Betz, 1986 and Betz et al, 1994, incorporated herein in their entirety by reference.
The BBB was initially observed by Ehrlich when he observed what he termed “lower affinity” of vital dyes for the brain than other tissue. Goldmann in 1913 however, determined the actual presence of a barrier by showing that the vital dye trypan blue when injected directly into the brain stained the brain but did not leave the CNS. These early experiments by Golmann and others established that the CNS is separated from the bloodstream by blood-brain and blood-cerebrospinal fluid (CSF) barriers.
The BBB impedes the delivery of drugs to the CNS. Methods have been designed to deliver needed drugs such as direct delivery within the CNS by intrathecal delivery can be used with, for example, an Ommaya reservoir. U.S. Pat. No. 5,455,044 provides for use of a dispersion system for CNS delivery or see U.S. Pat. No. 5,558,852 for a discussion of other CNS delivery mechanisms as well as Betz et al [1994] and Goldstein and Betz [1986].
There has been some progress in designing drugs that utilize the structure and function of the BBB itself to deliver the drugs. These drugs are designed to be lipid soluble or to be “piggy-backed” into the CNS by being coupled to peptides that can cross the BBB through mediated transport mechanisms. However, not all drugs are amenable to this solution. Partridge and his colleagues have worked extensively in this area. Pharmacological formulations that cross the blood-brain barrier can be administered. [Brem et al., 1993] Such formulations can take advantage of methods now available to produce chimeric peptides in which the present invention is coupled to a brain transport vector allowing transportation of these engineered drugs across the barrier [Pardridge, et al., 1992; Pardridge, 1992; Bickel, et al., 1993]. See also The Exonomist, Jan. 4, 1997.
In the disease process, the BBB is often disrupted. For example in meningitis, Tuomanen [1993] has shown that the response against the bacterial infection lead to a breach of the BBB. Further, in trauma and brain tumors the BBB is often disrupted as well as exposure to certain agents such as soman [Lallement et al, 1991; Petrali et al, 1991]. Disruption has been shown in ischemia [Burst, 1991] and in Alzheimer's Disease [Harik and Kalaria, 1991].
In appropriate cases the blood-brain barrier disruption can be utilized to deliver drugs to the CNS, as for example osmotic disruption [Neuwelt et al., 1980a]. However, generally this is not the case since, for example, exposure to soman is accompanied by seizures [Petrali et al, 1991].
However, while these methods do provide CNS delivery for some drugs it would be useful to have additional means of delivery. In particular it would be useful to have mechanisms that temporarily and reversibly open the BBB to allow non-engineered drugs through.
Stress has been shown to affect the permeability of the BBB [Sharma, et al, 1991; Ben-Nathan, et al, 1991]. Further, in mammals, acute stress elicits a rapid, transient increase in released acetylcholine (ACh) with a corresponding phase of increased neuronal excitability [Imperato, et al, 1991]. There have been some studies showing that the pharmacological blockade of acetylcholine—hydrolyzing enzyme, acetylcholine esterase (AChE) promotes a similar enhancement in electrical activity in cortical neurons [Ennis and Shipley, 1992].
AChE has three splice variant AChEmRNAs (FIG.
1
). Alternative splicing controls the generation of proteins with diverse properties from single genes through the alternate excision of intronic sequences from the nuclear precursors of the relevant mRNAs (Pre-mRNA). It is known to be cell type-, tissue- and/or developmental stage-specific and is considered as the principal mechanism controlling the site(s) and timing of expression and the properties of the resultant protein products from various genes.
Three alternative AChE-encoding mRNAs have been described in mammals (FIG.
1
). The dominant brain and muscle AChE (AChE-T) is encoded by an mRNA carrying exon E1 and the invariant coding exons E2, E3, and E4 spliced to alternative exon E6. AChEmRNA bearing exons E1-4 and alternative exon E5 encodes the glycolipid phosphatidylinositol (GPI)-linked form of AChE characteristic of vertebrate erythrocytes (AChE-H). An additional readthrough mRNA (AChE-I4) species (Table 1, SEQ ID No:1) retaining the intronic sequence I4 (SEQ ID No:2;
FIG. 2
) located immediately 3′ to exon E4 is found in rodent bone marrow and erythroleukemic cells and in various tumor cells lines of human origin. (The book
Human Cholinesterases and Anticholinesterases
by Soreq and Zakut (Academic Press, Inc., 1993) provides a summation of the biochemical and biological background as well as the molecular biology of human cholinesterase genes and the proteins. The book in its entirety is incorporated herein by reference.)
It would be useful to facilitate transport through the BBB by using a stress mimicking agent to have a controlled reversible disruption, or opening, of the BBB and/or blood-CSF.
SUMMARY OF THE INVENTION
According to the present invention, a pharmaceutical composition for facilitating passage of compounds through the blood-brain barrier comprising the ACHE-I4 readthrough (SEQ ID No:1) splice variant or the I4 peptide (SEQ ID No:2) and analogues of each thereof and a pharmaceutically acceptable carrier is disclosed. Alternatively, the pharmaceutical composition for facilitating passage of compounds through the blood-brain barrier can comprise adrenaline, atropine and dopamine and a combination of dopamine and propanolol and a pharmaceutically acceptable carrier. Combinations of these agents can also be used.
The composition of the present invention can optionally include the compound to be transported across the BBB. Alternatively, the compound can be co-administered (simultaneously) with the composition or can be administered at some point during the biologically effective period of the action of the composition. That is the composition facilitates disruption of the BBB, i.e. opens the BBB, for a period depending on the dose and the compound can be administered during this relevant period.
The present invention provides a method for administering a compound to the CNS of an animal by subjecting the animal to a stress-mimicking agent or treatment. This agent or treatment facilitates disruption of the blood-brain barrier. During the period that the BBB is opened or disrupted a compound can be administer such that the compound is enabled to passage through the disrupted BBB into the CNS.
The method and composition of the present invention therefore provides for delivery to the central nervous system of compounds that are necessary for treatment modalities in any condition affecting the central nervous system where the blood-brain barrier would impede the delivery of the compound. These conditions can include any disease or pathology of the central nervous system and can includ
Friedman Alon
Kaufer Daniela
Siedman Shlomo
Soreq Hermona
Borin Michael
Kohn & Associates
Yissum Research Development Company
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