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AssigneeMount Sinai School of Medicine of New York University
InventorsDan Felsenfeld, Maria Diverse-Pierluissi
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The present invention pertains to methods to promote outgrowth of, or extension across a substrate of, neuronal cells by inhibiting the interaction between the cytoplasmic tail of the L1-CAM cell surface adhesion molecule and the cytoskeletal protein ankyrin. The invention also pertains to a method to treat diseases characterized by axonal damage such as spinal cord injury, traumatic brain injury, stroke, and neurodegenerative disease by administration of novel peptides that inhibit the binding of the L1-CAM cytoplasmic tail to ankyrin, and to pharmaceutical compositions comprising such peptides. The present invention pertains to the regulation of neuronal signal propagation. Addition of the peptide of the invention disrupts the interaction between the cytoplasmic tail of the cell surface adhesion molecule L1-CAM, the cytoskeletal protein ankyrin, and voltage-gated calcium channels at the presynaptic surface of a neuron leading to a transient redistribution of the calcium channels to cytoplasmic vesicles. This redistribution blocks signal propagation as demonstrated by the inhibition of voltage gated calcium current and a decreased secretion of Substance P, which mediates pain signaling. Furthermore, the invention pertains to a method of blocking calcium flux to protect against neural cell death following stroke or traumatic head injury.
A method for promoting outgrowth of a mammalian neuron comprising inhibiting the binding of an ankyrin protein of said neuron to an L1-CAM protein, by contacting said neuron with a peptide comprising the amino acid sequence set forth in SEQ ID NO:
A method for promoting extension of a mammalian neuronal cell across a substrate comprising inhibiting the binding of an ankyrin protein of said neuron to an L1-CAM protein of said neuron, by contacting said neuron with a peptide comprising the amino acid sequence set forth in SEQ ID NO:
A method for treating diseases characterized by axonal damage selected from spinal cord injury, traumatic brain injury, stroke, and neurodegenerative disease, which comprises administering to a mammal in need of such treatment an effective amount for treating said diseases of a peptide comprising the sequence set forth in SEQ ID NO:
A pharmaceutical composition for treating diseases characterized by axonal damage selected from spinal cord injury, traumatic brain injury, stroke, and neurodegenerative disease comprising peptide comprising the sequence set forth in SEQ ID NO:
An isolated peptide comprising an amino acid sequence consisting of SEQ ID NO:
An isolated peptide comprising an amino acid sequence consisting of SEQ ID NO:
An isolated nucleic acid encoding the peptide comprising an amino acid sequence consisting of SEQ ID NO:
A method of inhibiting neuronal signaling in a mammal which comprises disrupting the interaction between L1-CAM, ankyrin, and voltage-gated calcium channels, by contacting a neuron with a peptide comprising the amino acid sequence set forth in SEQ ID NO:
A method for treating pain in a mammal comprising disrupting the interaction between L1-CAM, ankyrin, and voltage-gated calcium channels in a subject in need of such treatment, which comprises administering an amount effective for the treatment of pain of a peptide comprising the sequence set forth in SEQ ID NO:
The method of claim 14, which comprises administering the composition locally in the vicinity of the affected neurons.
The method of claim 14, which comprises administering the composition with an osmotic pump.
The method of claim 18, which comprises situating the osmotic pump for administration of the composition to a region of the dorsal spinal cord.
A method for preventing neuronal cell death after an ischemic attack or stroke in a mammal comprising disrupting the interaction between L1-CAM, ankyrin, and voltage-gated calcium channels in a subject in need of such treatment [which comprises administering to a subject in need of such treatment for an amount effective for the prevention of neuronal cell death of a peptide comprising the amino acid sequence set forth in SEQ ID NO:
A method for blocking neuronal calcium flux in a mammal comprising disrupting the interaction between L1-CAM, ankyrin, and voltage gated calcium in a subject in need of such treatment.
Dependencies are inferred from the claim text.