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Seoul, South Korea

Duong T.,Chonnam National University | Kim J.,Chung - Ang University | Ruley H.E.,Vanderbilt University | Jo D.,Chonnam National University | And 2 more authors.
PLoS ONE | Year: 2014

Parkinson's disease (PD) is a neurodegenerative disorder of complex etiology characterized by the selective loss of dopaminergic neurons, particularly in the substantia nigra. Parkin, a tightly regulated E3 ubiquitin ligase, promotes the survival of dopaminergic neurons in both PD and Parkinsonian syndromes induced by acute exposures to neurotoxic agents. The present study assessed the potential of cell-permeable parkin (CP-Parkin) as a neuroprotective agent. Cellular uptake and tissue penetration of recombinant, enzymatically active parkin was markedly enhanced by the addition of a hydrophobic macromolecule transduction domain (MTD). The resulting CP-Parkin proteins (HPM13 and PM10) suppressed dopaminergic neuronal toxicity in cells and mice exposed to 6-hydroxydopamine (6-OHDH) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). These included enhanced survival and dopamine expression in cultured CATH.a and SH-SY5Y neuronal cells; and protection against MPTP-induced damage in mice, notably preservation of tyrosine hydroxylase-positive cells with enhanced dopamine expression in the striatum and midbrain, and preservation of gross motor function. These results demonstrate that CP-Parkin proteins can compensate for intrinsic limitations in the parkin response and provide a therapeutic strategy to augment parkin activity in vivo. © 2014 Duong et al.

ProCell Therapeutics Inc. | Date: 2014-01-03

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The present invention relates to an improved macromolecule transduction domain (MTD), which facilitates permeating the cell membrane of a biologically active molecule, having enhanced cell permeability. Specifically, an improved MTD according to the present invention, compared to an existing MTD, can transmit various types of biologically active molecule from inside the body and inside a test tube more effectively, and thus can be effectively used in a method to genetically alter a biologically active molecule so as to have cell permeability or in a method to transport a biologically active molecule into a cell, or the like. Additionally, the improved MTD can be very useful in development of new drugs and incrementally modified drugs as uses of the improved MTD are possible in drug delivery systems, recombinant protein vaccines or DNA/RNA therapeutic agents, gene or protein therapies, and pharmacologically or medically useful protein production or medical, pharmacological and pharmaceutical compositions.

The present invention relates to a reprogramming transcription factor recombinant protein in which a macromolecule transduction domain (MTD) is fused to a reprogramming transcription factor to obtain cell permeability. The present invention also relates to a polynucleotide for coding said reprogramming transcription factor recombinant protein and to an expression vector of said cell-permeable reprogramming transcription factor recombinant protein. Treating a somatic cell with the cell-permeable reprogramming transcription factor recombinant protein induces the reprogramming of the stem cell-specific gene of the somatic cell, and thus can be effectively used in the establishment of an induced pluripotent stem cell (iPS cell) having characteristics similar to those of an embryonic stem cell in terms of morphology and genetics.

Lim J.,ProCell Therapeutics Inc. | Lim J.,Sogang University | Duong T.,Chonnam National University | Do N.,Chonnam National University | And 8 more authors.
Clinical Cancer Research | Year: 2013

Purpose: Gastric cancer is a leading cause of cancer death worldwide. Limited therapeutic options highlight the need to understand the molecular changes responsible for the disease and to develop therapies based on this understanding. The goal of this study was to develop cell-permeable (CP-) forms of the RUNT-related transcription factor 3, RUNX3 - a candidate tumor suppressor implicated in gastric and other epithelial cancers-to study the therapeutic potential of RUNX3 in the treatment of gastric cancer. Experimental Design: We developed novel macromolecule transduction domains (MTD) which were tested for the ability to promote protein uptake by mammalian cells and tissues and used to deliver of biologically active RUNX3 into human gastric cancer cells. The therapeutic potential CP-RUNX3 was tested in the NCI-N87 human tumor xenograft animal model. Results: RUNX3 fusion proteins, HM57R and HM 85R containing hydrophobic MTDs enter gastric cancer cells and suppress cell phenotypes (e.g., cell-cycle progression, wounded monolayer healing, and survival) and induce changes in biomarker expression (e.g., p21Wa1 and VEGF) consistent with previously described effects of RUNX3 on TGF-β signaling. CP-RUNX3 also suppressed the growth of subcutaneous human gastric tumor xenografts. The therapeutic response was comparable with studies augmenting RUNX3 gene expression in tumor cell lines; however, the protein was most active when administered locally, rather than systemically (i.e., intravenously). Conclusions: These results provide further evidence that RUNX3 can function as a tumor suppressor and suggest that practical methods to augment RUNX3 function could be useful in treating of some types of gastric cancer. © 2012 American Association for Cancer Research.

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