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PTD-SMAD7 therapeutics

A nucleic acid molecule, human technology, used in anti-inflammatory agents, non-central analgesics, retro RNA viruses, etc.

Active Publication Date: 2016-02-24
UNIV OF COLORADO THE REGENTS OF
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Additionally, the effects of Smad7 may not always be explained by its role in TGF-β signaling

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0243] Example 1: K5.Smad7 mice are resistant to oral mucositis

[0244] A transgenic mouse model expressing human Smad7 protein in keratinocytes (K5.Smad7) was generated as previously described (Han et al., Dev. Cell, 11:301-312, 2006). Confirmation of transgene expression in oral epithelium ( Figure 7A -B). Mice were bred into the C57BL / 6 background, and 8-10 week old male and female transgenic mice as well as wild-type littermates were used in the study. These mice showed improved healing of excised skin wounds (Han et al., Am. J. Pathol., 179:1768-1779, 2011) and radiation-induced oral mucositis.

[0245] K5.Smad7 mice and wild-type littermates were exposed to cranial radiation to determine the bioequivalent dose (BED) required to induce oral mucositis in mice. It was determined that 8Gy x 3 (BED = 43.2), a regimen clinically associated with hypofractionated radiation therapy, was the minimum dose required to induce oral mucositis ( Figure 1A -B). To evaluate the ...

Embodiment 2

[0252] Example 2: Rac1 contributes to Smad7-mediated keratinocyte migration

[0253] To determine whether Smad7 contributes to the healing of human oral keratinocytes, Smad7 was knocked down in spontaneously immortalized human oral keratinocytes (NOK-SI). Smad7 knockdown attenuates keratinocyte migration after incision ( Figure 2D and Figure 8A ). Conversely, knocking down TGF-β1 accelerated keratinocyte migration ( Figures 8B-8D), which is consistent with the accelerated wound healing observed in mice lacking TGF-β1 or Smad3.

[0254] To investigate the molecular mechanism associated with Smad7-mediated keratinocyte migration, Rac1, a protein essential for oral wound healing, was examined. Rac1 decreased after Smad7 knockdown ( Figure 2E ). TGF-β1 overexpression in oral mucositis is expected to activate Rac1 via a Smad-independent mechanism. However, despite a 2-fold increase in total Rac1 protein after irradiation, activated Rac1 protein was not significantly al...

Embodiment 3

[0261] Example 3: Tat-Smad7 attenuates radiation-induced oral mucositis

[0262] The ability of the Smad7 transgene to block multiple pathological processes of oral mucositis prompted us to explore whether localized Smad7 delivery could be used to prevent and treat oral mucositis. Because Smad7 is a nuclear protein, localized Smad7 delivery requires allowing rapid entry of Smad7 into cells before saliva washes away the protein. Therefore, recombinant human Smad7 was generated with an N-terminal Tat tag, which allows the protein to rapidly permeate the cell membrane and enter the nucleus. The V5 epitope was added to the C-terminal end of the Tat-Smad7 protein to track Tat-Smad7 cell penetration ( Figures 11A-11D ).

[0263] Tat-Smad7 biological activity was tested using its ability to block Smad2 phosphorylation ( Figure 11C ). A Tat-Cre recombinant protein with the same tag as the control was produced ( Figure 11E -F) and cloned into the pET101-Topo protein expressio...

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Abstract

The present technology provides methods and compositions for the treatment of inflammatory and / or tissue damage conditions. In particular, the use of Smad7 compositions delivered locally or systemically to a site of inflammation and / or tissue damage is described. Other specific embodiments concern treatment or prevention of side effects caused by radiation and / or chemotherapy, including but not limited to oral and gastric mucositis. Also provided are codon-optimized nucleic acids encoding for Smad7 fusion proteins.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Patent Application USSN 61 / 775,252, filed March 8, 2013, which is hereby incorporated by reference in its entirety. [0003] Statement of Government Interest [0004] This invention was made with government support under Grant Number AR061796 awarded by the National Institutes of Health. The government has certain rights in this invention. Background technique [0005] Oral mucositis, a type of severe mouth sores, is a common side effect of high-dose radiation used for bone marrow transplantation or craniofacial radiation therapy for cancer. Severe oral mucositis may require feeding tubes, management of severe pain, and premature discontinuation of radiation therapy. Excessive inflammation and epithelial ablation are key features of oral mucositis. [0006] Palifermin, a KGF (human keratinocyte growth factor) recombinant protein, is approved for the prevention of ...

Claims

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Application Information

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IPC IPC(8): C12P19/34
CPCA61K48/005C07K14/4702C07K2319/10C07K2319/23C12N2800/22A61K38/00A61K38/162A61K38/18A61P1/02A61P17/02A61P17/06A61P29/00A61P37/02C07K14/4703C07K2319/20C07K14/005C07K14/475C12N7/00C12N2740/16311C12N2740/16322
Inventor 王晓京张庆红优素福·里法利
Owner UNIV OF COLORADO THE REGENTS OF
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