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Targeted delivery of glycine receptors to excitable cells

a glycine receptor and excitable cell technology, applied in the direction of dsdna viruses, peptide/protein ingredients, drug compositions, etc., can solve the problems of affecting the normal function of excitable cells, and affecting the ability of excitable cells to function normally, so as to reduce formalin-induced nociceptive behavior, and alleviate observed pain

Inactive Publication Date: 2008-11-20
UNIVERSITY OF PITTSBURGH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0009]FIG. 4A is a graph demonstrating that exogenously applied glycine reduces formalin-induced nociceptive behavior in rats following injection of a GlyR-expressing HSV vector.
[0010]FIG. 4B is a graph demonstrat...

Problems solved by technology

However, the administration of ligands that act on endogenous ion channels poses significant hurdles because of the potential for widespread side effects due to systemic delivery.
Moreover, agents that act locally (such as silver or capsaicin) have unwanted side effects and can potentially cause permanent damage.
For use in vertebrates, and particularly in human patients, however, this approach poses a risk of generating an immune response against such a foreign protein, leading to potential autoimmune disorders.

Method used

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  • Targeted delivery of glycine receptors to excitable cells
  • Targeted delivery of glycine receptors to excitable cells
  • Targeted delivery of glycine receptors to excitable cells

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0041]This example demonstrates targeted delivery of glycine receptors to peripheral neurons as treatment for pain.

[0042]Production of recombinant virus. The plasmid pSHB2-GlyR was created by cloning the GlyR sequences into plasmid SHB2 at the BamHI site of the polylinker. SHB2 was generated by ligation of a HCMV-BGHpA expression construct from pRC-CMV into plasmid pSASB3 at the unique BamHI site. pSASB3 was constructed by cloning the Sph I to Afl III (Sal I linkered) fragment (1928 bp) of the HSV-1 KOS strain genome (nucleotides 124485-126413) into Sph I / Sal I digested pSP72 followed by insertion of a the 695 bp BglII to BamHI fragment (nucleotides 131931 to 132626) containing regions upstream of the ICP4 promoter including the viral origin contained within the short inverted repeat regions into the BglII to BamHI sites of the vector plasmid. The parental virus vHG was created using the same targeting plasmid except that a HCMV-eGFP construct was cloned into the same BamHI site res...

example 2

[0052]This example demonstrates a method for inhibiting pain in vivo comprising exogenously expressing a GlyR protein.

[0053]The analgesic efficacy of vHGlyRα1 will be assessed in three mouse pain models: (1) the formalin footpad model of acute inflammatory pain, (2) the complete Freund's adjuvant (CFA) model of chronic inflammatory pain, (3) spinal nerve ligation model, (4) the chronic constriction injury (CCI) model of chronic neuropathic pain, and (5) osteolytic sarcoma model of bone cancer pain. Each of these pain models is described in detail below.

[0054]Formalin footpad test (FFT): This is an acute model of inflammatory pain (Dubisson and Dennis, Pain, 4(2): 161-74 (1977)). 50 μl of 2.5% formalin will be injected subcutaneously into the plantar surface of the right hind foot. This will cause acute pain lasting approximately 1-2 hours. Following formalin injection, each animal will be placed in a clear rectangular plexiglass cage (20 cm wide×60 cm long×20 cm high). Different pos...

example 3

[0064]This example demonstrates a method of generating a transgenic animal that exogenously expresses a GlyR protein.

[0065]A cb-stop-lacZ construct (Zinyk et al., Curr Biol., 8(11):665-8 (1998)) will serve as the base construct for production of transgenic mice. This construct contains (5′ to 3′) the constitutively active chicken β-actin promoter and the first two non-coding exons, a transcription / translation stop cassette that is flanked by loxP sequences, a lacZ reporter cassette, and the 3′ untranslated region / polyadenylation site from the mouse protamine-1 gene. In previous studies of transgenic mice that harbor this construct (see, e.g., Zinyk et al., supra), it was demonstrated that in the absence of Cre-mediated recombination, the reporter cassette was inactive. Following Cre-mediated recombination and deletion of the stop cassette, the reporter cassette was expressed.

[0066]Standard molecular techniques will be used to replace the lacZ reporter with either a wild-type or a mu...

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Abstract

The invention provides a method of modulating electrophysiological activity of an excitable cell. The method involves causing exogenous expression of a glycine receptor (GlyR) protein in an excitable cell of a subject. Thereafter, the excitable cell is exposed to an allosteric modulator of the GlyR protein. Modulation of the exogenous GlyR protein (an ion channel) in response to the allosteric modulator modulates the electrophysiological activity of the excitable cell. The method can be used to control pain in a subject. The invention further provides a replication-defective HSV vector comprising an expression cassette encoding a GlyR protein, stocks and pharmaceutical compositions containing such vectors, and a transgenic animal.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This patent application claims the benefit of U.S. Provisional Patent Application No. 60 / 917,752, filed May 14, 2007 which is incorporated by reference.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT[0002]This invention was made with Government support under Grant Number DK044935-11 awarded by the National Institute of Diabetes and Digestive and Kidney Diseases. The Government has certain rights in this invention.BACKGROUND OF THE INVENTION[0003]The potential to modulate the electrophysiological response of excitable cells (such as neurons and muscle cells) could potentially lead to treatment of neuromuscular conditions, pain, and other disorders associated with the activity of such cells. However, the administration of ligands that act on endogenous ion channels poses significant hurdles because of the potential for widespread side effects due to systemic delivery. Moreover, agents that act locally (such as silver or cap...

Claims

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Application Information

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IPC IPC(8): A01K67/027C12N5/06A61P25/02A61K31/7088
CPCA01K2217/20A01K2227/105A01K2267/0356A01K2267/0393A61K38/00C07K14/705C12N15/86C12N2710/16643C12N2800/30A61K48/005A61P25/00A61P25/02A61P29/00A01K67/0278A01K2217/206C12N7/00
Inventor CASCIO, MICHAELGLORIOSO, III, JOSEPH C.GOSS, JAMES R.KRISKY, DAVID
Owner UNIVERSITY OF PITTSBURGH
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