Method and composition for treating neuropathic pain

A neurological, compositional technology, applied in the field of combined treatment regimens, able to solve the problems of not allowing to limit the treatment effect of spinal cord segments, without chronic neuropathic pain, etc.

Pending Publication Date: 2020-05-01
RGT UNIV OF CALIFORNIA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are no gene therapy-based technologies available for the treatment of chronic neuropathic pain
Similarly, there are currently no gene therapy-based techniques that can be effectively used to inhibit nociceptive transmission in specific spinal cord segments ipsilateral to the site of peripheral nerve injury.
Furthermore, currently available spinal drug delivery systems, such as epidural delivery or intrathecal delivery, do not allow limiting the therapeutic effect of spinal cord segments

Method used

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  • Method and composition for treating neuropathic pain
  • Method and composition for treating neuropathic pain
  • Method and composition for treating neuropathic pain

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0137] Vector delivery in mouse models

[0138] Figure 1A with Figure 1B The subpial delivery of an AAV9 (or Anc80) vector encoding GAD65 (glutamate decarboxylase 65) and VGAT (vesicular GABA transporter) into the targeting segment is exemplified. One-third to one-half the diameter of the sciatic nerve of blank C57BL6 mice was tightly ligated (unilateral ligation) to induce mechanical allodynia. Animals were tested for changes in tactile nociceptive thresholds using von Frey filaments and brush-induced allodynia over a 10-day period following nerve injury.

[0139] Ten days after induction of sciatic nerve injury, animals received a unilateral subpial injection of AAV9 encoding the GAD65 and VGAT genes under the ubiquitin promoter (UBI). Two control groups were studied. In the first control group, animals with sciatic nerve injury were injected subpially at L2-L3 only with PBS. In another control group (uninjured blank animals), no treatment was given. In a separate grou...

Embodiment 2

[0146] Vector delivery in a porcine model

[0147] In this example, an adult pig model is used to demonstrate that subpial delivery of vectors achieves well-targeted transgene expression in an animal species with spinal cord dimensions similar to those of adults. Adult pigs (Yugatan pigs, 15kg to 25kg; n=3) received unilateral subpial (L2-L3) Anc80-UBI-Rpl22-3xHA vector delivery (100 μl; 1.2×10 13 gc / ml). Animals survived for 48 hours after vehicle injection and were then perfused with 4% paraformaldehyde for fixation. Transverse spinal cord sections were then prepared and stained with anti-HA antibody. Stained sections were analyzed by confocal microscopy. Such as Figure 5A to Figure 5D As shown, dorsal horn neuron-specific Rp122 protein expression was observed on the same side as the vector-injected side.

[0148] Another group of adult pigs (Göttingen-Minnesota; 35kg to 45kg; n=3) received unilateral subpial (L2-L3) Anc80-UBI-GAD65 / VGAT (100 μl; 1.2×10 13 gc / ml) to d...

Embodiment 3

[0151] Vector delivery in a rat model of chronic muscle spasticity

[0152] In a rat model of chronic muscle spasticity (ie, rats with spinal cord-induced muscle spasm), vehicle treatment was provided to demonstrate antispasticity following subpial delivery of AAV9-UBI-GAD65 / VGAT. Such as Figure 8A with Figure 8B As shown, muscle spasms measured in animals receiving a control vector (AAV9-GFP) showed a gradual increase in muscle spasms over 8 weeks after virus delivery (compared to baseline measured 2 to 3 months after spinal cord transection). In contrast, a near complete blockade of the spastic response was measured in animals receiving the AAV9-UBI-GAD65 / VGAT vector. Measurements of H-reflex frequency-dependent inhibition (RDD) revealed a significant restoration of RDD in animals treated with the AAV9-UBI-GAD65 / VGAT vector ( Figure 8C with Figure 8D ).

[0153] Bilateral (L2-L4) subpial AAV9-UBI-GAD65 / VGAT delivery induces a mixed inhibitory-excitatory neurotransmi...

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Abstract

The present invention provides a therapy for treating neuropathic pain by subpial administration of small quantities of a composition for spinal segment-specific upregulation of GAD65 (glutamatedecarboxylase) gene and VGAT (vesicular GABA transporter) gene, which is effective for induction of nociceptive effects by potentiating release of vesicular GABA from infected dorsal horn neurons into the synaptic cleft.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of priority under 35 U.S.C. § 119(e) to U.S. Serial No. 62 / 556,088 filed September 8, 2017, the entire contents of which are incorporated herein by reference. [0003] sequence listing [0004] This application contains a Sequence Listing, which has been filed electronically in ASCII format and is hereby incorporated by reference in its entirety. The ASCII copy created on September 6, 2018 is named 20378-201844_SL.txt and is 22KB in size. technical field [0005] The present invention relates generally to the treatment of neuropathic pain, and more particularly to combination therapy regimens involving subpial delivery of one or more genes for the treatment of chronic neuropathic pain. Background technique [0006] Neuropathic pain is pain caused by various types of nerve damage. Some examples of neuropathic pain disorders include, but are not limited to, diabetic peripheral neuro...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K48/00C12N9/88C07K14/435
CPCC07K14/705C12Y401/01015C12N9/88A61K48/005A61K48/0058C12N2750/14143A61P25/04A61P29/00A61P25/02A61K9/0019A61K35/761A61K38/1787A61K38/51A61K48/0025A61K48/0075C12N7/00C12N15/86C12N2750/14171
Inventor 马丁·马尔萨拉宫之原厚司田所孝广
Owner RGT UNIV OF CALIFORNIA
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