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Peripherally delivered glutamic acid decarboxylase gene therapy for spinal cord injury pain

a glutamic acid decarboxylase and spinal cord injury technology, applied in the direction of lyases, dsdna viruses, peptide sources, etc., can solve the problems of long pain, impede effective rehabilitation, adversely affect the quality of life,

Inactive Publication Date: 2014-09-11
UNIVERSITY OF PITTSBURGH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The invention is a vector, like a herpes simplex virus, that contains a piece of DNA that makes a protein called glutamic acid decarboxylase (GAD). The invention also includes a stock of these vectors and a pharmaceutical composition containing them. The invention further includes a method to treat pain, specifically spinal cord injury pain or peripheral neuropathic pain, in mammals by giving them a vector with the GAD DNA. The technical effect of this invention is the ability to provide a tool for treating pain by delivering a specific protein to the spinal cord or peripheral nerves.

Problems solved by technology

Pain following spinal cord injury is an important problem that adversely impacts quality of life and impedes effective rehabilitation.
Chronic SCI pain persists for long periods of time and often does not respond well to conventional pain treatment.
The level of SCI pain can range from a mere annoyance to being unbearable for the patient.
The former is often present during the early stages of spinal cord injury and resolves over time, while the latter develops gradually and is generally refractory to medical treatment.
Chronic SCI pain following spinal cord injury is an important problem that adversely impacts quality of life and impedes effective rehabilitation.
It often becomes worse with movement and eases with rest.
GABA agonist drugs (e.g. baclofen) are approved for treatment of selected neuropathic pain syndromes, but the ubiquitous distribution of GABA receptors in the central nervous system results in side effects that impose severe restrictions on administering baclofen, even when administered intrathecally.
However, the vectors in these studies were injected directly into neuronal nuclei of the brain but not used in pain models or experimentation.
Currently, there are no uniformly successful medical or surgical treatments for SCI pain.
The response rates to these treatments are often limited by side effects.
Unfortunately, neuropathic SCI pain does not usually respond to opioids (e.g., morphine).
These procedures ultimately raise the level of SCI pain and may worsen neuropathic SCI pain over the long term.
Peripheral neuropathic pain is another common and difficult to treat concomitant of polyneuropathy or structural nerve injury.
Opioids are relatively ineffective, and their use is limited by side effects.
Antidepressants and anticonvulsants have demonstrated efficacy in randomized controlled trials but provide only 50% relief in less than half of patients treated.
GABAergic agents have not been widely used in the treatment of neuropathic pain because the therapeutic window of these agents is modest and the dose is limited by side effects.

Method used

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  • Peripherally delivered glutamic acid decarboxylase gene therapy for spinal cord injury pain
  • Peripherally delivered glutamic acid decarboxylase gene therapy for spinal cord injury pain
  • Peripherally delivered glutamic acid decarboxylase gene therapy for spinal cord injury pain

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0059]This example demonstrates the construction of the GAD vector.

[0060]The nonreplicating HSV vector QHGAD67 is defective in expression of the HSV immediate early (IE) genes ICP4, ICP22, ICP27, and ICP47, and contains the human GAD67 gene under the control of the human cytomegalovirus immediate early promoter (HCMV IEp) in the UL41 locus (FIG. 1). Control vector Q0ZHG (constructed according to the method described in Chen et al. J. Virol, 74(21), 10132-41 (2000)) is defective in the same genes, but contains the Escherichia coli lacZ reporter gene in the same position (FIG. 1).

[0061]GAD67 cDNA (constructed according to the method described in Bu, D. F., et al., Proc. Natl. Acad. Sci. USA, 89, 2115-2119 (1992)) was individually sub-cloned as a ClaI / Xbal fragment downstream of the human cytomegalovirus immediate early promoter in the shuttle plasmid p41H, containing the promoter and adequate HSV flanking DNA sequence in order to enable efficient homologous recombination at the UL41 g...

example 2

[0062]This example demonstrates the construction of an HSV vector having extended deletions of the ICP4 and ICP27 loci and a deletion of UL55.

[0063]The schematic for constructing this vector is set forth in FIG. 14. Specifically, plasmid d106 (Hadjipanayis and DeLuca, Can Res 65(12): 5310-6 (2005)) was virally crossed with plasmid TOZ.1 (Arafat et al., Clin Can Res 6: 4442-8 (2000)) to produce QOZHG.1. The details of vector QOZHG.1 are described in Example 1 and its construction described in Chen et al., J Virol 74(21), 10132-41 (2000).

[0064]Plasmid pPXE (Niranjan et al., Mol Ther 8(4):530-42 (2003)) was recombined into the ICP27 locus of QOZHG.1 to rescue the previous ICP27 deletion and to remove HCMV-eGFP gene. A single recombinant was then isolated, purified and verified by selecting a plaque that did not exhibit green fluorescence under a fluorescent microscope. The recombinant was termed E1. E1 was negative for the GFP gene and positive for the LacZ gene.

[0065]Plasmid 41HN was ...

example 3

[0079]This example demonstrates the expression of GAD protein by GAD vector transduced cells.

[0080]One week after subcutaneous inoculation of QHGAD67 into the plantar surface of the hind paw of a laboratory rat the amount of GAD67 mRNA in the pooled L4-L6 DRG detected by real-time RT-PCR was fivefold greater than in contralateral DRG transduced with Q0ZHG (FIG. 2). Also, GAD67 immunoreactivity in transduced DRG was present in neurons in a broad spectrum of DRG neurons of all sizes compared to the contralateral (vehicle-injected) DRG. GAD67 protein, determined by Western blot, was significantly increased in both the lumbar DRG (0.048±0.009 OD units) compared to sham-inoculated controls (0.025±0.006 OD units, P<0.01.

[0081]One week after subcutaneous inoculation of 30 μl of 11×109 pfu / ml QHGAD67 increased immunoreactivity was seen predominantly in laminae II and III compared to the contralateral (vehicle-injected) dorsal horn. In the superficial dorsal horn of control rats GAD67 immuno...

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Abstract

The invention provides a method of treating spinal cord injury pain or peripheral neuropathic pain in a mammal comprising administering to a mammal a vector comprising a nucleotide sequence encoding a glutamic acid decarboxylase (GAD) protein in an amount effective to treat spinal cord injury pain or peripheral neuropathic pain.

Description

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT[0001]This invention was made in part with Government support under Grant Numbers NS044507, NS38850 and NS43247, awarded by the United States National Institute of Neurological Disorders and Stroke and a Research Grant from the Department of Veterans Affairs. The Government may have certain rights in this invention.FIELD OF THE INVENTION[0002]This invention pertains to a method and composition for treating pain.BACKGROUND OF THE INVENTION[0003]Pain following spinal cord injury is an important problem that adversely impacts quality of life and impedes effective rehabilitation. Almost every patient that suffers from a spinal cord injury (SCI) suffers from SCI pain. SCI pain can be at the level of injury or below the level of injury. With each person, the pain varies in intensity, frequency, duration of episodes, and the type of pain experienced. The type of pain experienced has been described by patients as a tingling, nu...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C12N15/86
CPCC12N15/86C12N9/88C12N2710/16643C12N2840/20C12Y401/01015A61P25/04C12N15/64C07K14/435C12N15/09
Inventor GLORIOSO, JOSEPH C.FINK, DAVID J.WOLFE, DARRENKRISKY, DAVID
Owner UNIVERSITY OF PITTSBURGH
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