Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1998-08-18
2001-11-06
Low, Christopher S. F. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S021800, C530S350000, C530S399000, C424S185100, C424S195110
Reexamination Certificate
active
06313089
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to compositions comprising complexes of apolipoprotein E and ciliary neurotrophic factor, and methods of administering the same.
BACKGROUND OF THE INVENTION
Apolipoprotein E (protein: apoE; allele: APOE) is the principal apolipoprotein in the brain (for review, see Mahley, (1988)
Science
240, 622) and cerebrospinal fluid (CSF) (Pitas et al., (1987)
J. Biol. Chem
. 262, 14352). Several observations have implicated a role for apoE in the injured nervous system. Expression of apoE mRNA by astrocytes in the hippocampus increases following entorhinal cortex lesion (Poirier et al., (1991)
Mol. Brain Res
. 11, 97). Oligodendrocytes and macrophages increase expression of apoE following optic and sciatic nerve injury, respectively (optic: Stoll et al., (1989)
GLIA
2, 170; sciatic: Skene and Shooter, (1983)
Proc. Nat. Acad. Sci. USA
80, 4169; Stoll and Mueller, (1986)
Neurosci. Lett
. 72, 233), and apoE protein accumulates to 5% of total extracellular protein following peripheral nervous system (PNS) injury (Skene and Shooter, (1983)
Proc. Nat. Acad. Sci. USA
80, 4169). APOE is a susceptibility gene for familial and late-onset Alzheimer's disease (AD: Strittmatter et al., (1993)
Proc. Nat. Acad. Sci. USA
90, 1977; for review see Strittmatter and Roses, (1995)
Proc. Nat. Acad. Sci. USA
92, 4725). The gene dose of APOE4, one of the three major alleles of APOE in humans, is correlated with increased risk and decreased average age of onset of AD. These observations suggest a role for apoE in the injured or diseased nervous system.
Three major isoforms of apoE in humans—apoE2, apoE3 and apoE4—are distinguished by cysteine-arginine substitutions at positions 112 and 158. The most common isoform, apoE3, is secreted as a 299 amino acid protein with a single cysteine at position 112 and an arginine at position 158; apoE2 contains a cysteine at position 158 and apoE4 contains an arginine at position 112. ApoE contains two distinct structural and functional domains, a hydrophobic domain and a hydrophilic receptor binding domain (Weisgraber, (1994)
Adv. Prot. Chem
. 45, 249). The crystal structure of the hydrophilic domain of apoE is homologous to the family of four-helix bundle growth factors, including ciliary neurotrophic factor, although the sequences of these proteins diverge greatly. CNTF; reviewed by Bazan, (1991)
Neuron
7, 197; Mott and Campbell, (1995)
Curr. Opin. Struc. Biol
. 5, 114; apoE crystal structure by Wilson et al., (1991)
Science
252, 1817; CNTF crystal structure by McDonald et al., (1995)
EMBO J
. 14, 2689.
The cellular expression pattern of CNTF parallels that of apoE. CNTF expression in astrocytes is upregulated near sites of injury in the CNS (Ip et al., (1993)
Eur. J. Neurosci
. 5, 25) and myelinating Schwann cells in the PNS contain high levels of cytoplasmic CNTF (Rende, et al., (1992)
GLIA
5, 25) that is released following nerve injury. CNTF immunoreactivity and biologic activity in peripheral nerve are detectable extracellularly for 7 days following PNS injury (Sendtner et al., (1992)
J. Cell Biol
. 118, 139). CNTF exerts a broad range of biological activities, many of which suggest that CNTF acts as an injury-associated survival factor in the nervous system (reviewed by Adler, (1993)
Curr. Opin. Neurobio
. 3, 785). In vivo, CNTF supports the survival of intermediolateral column spinal cord neurons after adrenal medulla lesion (Blottner et al., (1989)
Neurosci. Let
. 105, 316), reduces the axotomy-induced death of facial nucleus neurons (Sendtner et al., (1990)
Nature
345, 440) and potentiates peripheral nerve regeneration (Sahenk et al., (1994)
Brain Res
. 655, 246). In vitro, CNTF promotes the survival of many neuronal cell types, including: sensory and sympathetic ganglion neurons of the PNS (sensory: Skaper and Varon, (1986)
Brain Res
. 389, 39; sympathetic: Saadat et al., (1989)
J. Cell Biol
. 108, 1807; cerebellar neurons: Larkfors et al., (1994)
Eur. J. Neurosci
. 6, 1015; and embryonic hippocampal neurons: Ip et al., (1991)
J. Neurosci
. 11, 3124).
CNTF has been used in vivo to protect striatal neurons in an animal model of Huntington's disease (Anderson et al., (1996)
Proc. Nat. Acad. Sci. USA
93, 7346). In this study, CNTF, but not BDNF, NGF or NT3, afforded protection against intrastriatal injection of the excitotoxin quinolinic acid. The best studied in vivo system for CNTF function is the peripheral nerve. Following unilateral transection of the sciatic nerve in postnatal day 5 mice there is a 66% loss of motoneurons (Kashihara et al., (1987)
J. Physiol
. (London) 386, 135; Snider et al., (1992)
J. Neurobiol
. 23, 1231) and a 33% loss of sensory neurons (Lo et al., (1995)
Exp. Neurol
. 134, 49) 10 days postsurgery. Local delivery of CNTF to the transection site rescues axotomized motor (Li et al., (1994)
J. Neurobiol
. 25, 759) and sensory neurons (Lo et al., (1995)
Exp. Neurol
. 134, 49). When the sciatic nerves of postnatal day 10 or adult mice are transected, no neuronal death is detected. One interpretation of these experiments is that Schwann cell derived CNTF is a survival factor for axotomized motor and sensory neurons. Because CNTF production by Schwann cells in the sciatic nerve increases dramatically over the first three weeks of postnatal development, the first postnatal week provides a window of time when Schwann cell derived CNTF is limited and survival after axotomy is partial.
Given that CNTF supports the growth, differentiation and survival of a wide variety of neuronal cell types, CNTF is an important candidate as a neuronal survival and regeneration factor following injury. Accordingly, there is a need in the art for strategies of potentiating the activity of CNTF to slow the progression of neurodegenerative diseases, to protect against neural degeneration after injury, and to facilitate nerve regeneration.
SUMMARY OF THE INVENTION
Disclosed herein is the novel discovery that apoE binds to and potentiates the biological actions of the neurotrophic factor CNTF.
As a first aspect, the present invention provides a composition comprising a complex of apolipoprotein E (apoE) and ciliary neurotrophic factor (CNTF). The apoE component can be apoE2, apoE3, or apoE4, and can be in a lipid-bound or delipidated state. Furthermore, the complex can be formed by either covalent or noncovalent interactions between the apoE and CNTF molecules.
As a second aspect, the present invention provides a method of enhancing the survival of neural cells, comprising administering to the neural cells a survival-enhancing amount of a composition comprising a complex of apolipoprotein E and ciliary neurotrophic factor. The claimed methods can be carried out both in vitro and in vivo.
As a third aspect, the present invention provides a method of administering a composition comprising a complex of apolipoprotein E and ciliary neurotrophic factor in a therapeutically-effective amount to a subject in need thereof.
These and other aspects of the invention are set forth in more detail in the description of the invention below.
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Ngo et al., ‘Computational Complexity , Potein Structure Prediction, And the Levinthal Paradox,’ The Protein Folding Problem and Tertiary Structuer Prediction. Ed. K. Merz and L. Le Grand. BirkHauser, Boston MA. pp. 491-495, 1994.*
Yuen et al. ‘Therapeutic Potential Of Neurotrophic Factors For Neurological Disorders’, Annals Neurology, vol. 40 No. 3, pp 346-354, Sep. 1996.*
Hefti, Franz. ‘Nerothrophic Factor Therapy For Nervous System Degerative Diseases’, Journal of Neurobiology, vol. 25, 11, pp. 1418-1435, 1994.*
Abstract: ‘Apolipoprotein E3 Binds To And Potentiates Teh Biologic Ac
Gutman Catherine R.
Matthew William D.
Strittmatter Warren J.
Duke University
Gupta Anish
Low Christopher S. F.
Myers Bigel Sibley & Sajovec P.A.
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