Odevixibat Treatment of Alagille Syndrome: A Case Report.

A male pediatric patient with elevated liver enzyme and bile acid levels, bile duct hypoplasia, mild liver fibrosis, and pruritus was initially diagnosed with progressive familial intrahepatic cholestasis. The patient did not respond to treatments of ursodeoxycholic acid and naltrexone. Subsequent treatment with odevixibat resulted in improvements in serum bile acid levels and pruritus within a few weeks of initiation.

Concise review: the involvement of SOX2 in direct reprogramming of induced neural stem/precursor cells.

Since induced pluripotent stem cells were first generated from mouse embryonic fibroblasts in 2006, somatic cell reprogramming has become a powerful and valuable tool in many fields of biomedical research, with the potential to lead to the development of in vitro disease models, cell-based drug screening platforms, and ultimately novel cell therapies. Recent research has now demonstrated the direct conversion of fibroblasts into stem, precursor, or mature cell types that are committed in their fate within a specific lineage, such as hematopoietic precursors or mature neurons. This has been achieved by ectopic expression of defined, tissue-specific transcription factors.

Stem cell-based therapy for Huntington's disease.

Huntington's disease (HD) is a late-onset neurodegenerative disease characterized by a progressive loss of medium spiny neurons in the basal ganglia. The development of stem cell-based therapies for HD aims to replace lost neurons and/or to prevent cell death. This review will discuss pre-clinical studies which have utilized stem or progenitor cells for transplantation therapy using HD animal models.

Characterization of Ku70(2)-NLS as bipartite nuclear localization sequence for non-viral gene delivery.

Several barriers have to be overcome in order to achieve gene expression in target cells, e.g. cellular uptake, endosomal release and translocation to the nucleus.

In vivo expression of interleukin-37 reduces local and systemic inflammation in concanavalin A-induced hepatitis.

We recently reported that after LPS stimulation, IL-37 translocates to the nucleus and reduces the expression of proinflammatory cytokines. The aim of this study was to investigate whether transiently expressed IL-37 in mice reduces inflammation in concanavalin A (ConA)-induced hepatitis and LPS-induced sepsis. Transgene IL-37 expression was detected in the liver lysate of mice injected with IL-37 plasmid-DNA after hydrodynamic tail vein injection.

Deviating from the well travelled path: precursor cell migration in the pathological adult mammalian brain.

The presence of both neural and glial precursor cells in the adult central nervous system (CNS) and the capacity of these cells to migrate through this mature structure to areas of pathological damage and injury raises hope for the development of new therapeutic strategies to treat brain injury and disease. Although at present time, the compensatory neurogenesis described after various types of brain pathologies appears to be modest, the development of a strategy promoting the directed mobilization and phenotypic induction of endogenous precursor cells to areas of neural cell loss remains of high interest. The development of such a strategy however is currently thwarted by a limited understanding of the process and factors influencing precursor cell migration.

Characterization of tailor-made copolymers of oligo(ethylene glycol) methyl ether methacrylate and N,N-dimethylaminoethyl methacrylate as nonviral gene transfer agents: influence of macromolecular structure on gene vector particle properties and transfection efficiency.

Oligo(ethylene glycol) methyl ether methacrylates (OEGMA) of various chain lengths (i.e., 9, 23, or 45 EG units) and N,N-dimethylaminoethyl methacrylate (DMAEMA) were copolymerized by atom transfer radical polymerization (ATRP), yielding well-defined P(DMAEMA-co-OEGMA) copolymers with increasing OEGMA molar fractions (F(OEGMA)) but a comparable degree of polymerization (DP approximately 120).

Optimization of Streptomyces bacteriophage phi C31 integrase system to prevent post integrative gene silencing in pulmonary type II cells.

phi C31 integrase has emerged as a potent tool for achieving long-term gene expression in different tissues. The present study aimed at optimizing elements of phi C31 integrase system for alveolar type II cells. Luciferase and beta-galactosidase activities were measured at different time points post transfection.

Self-assembly of ternary insulin-polyethylenimine (PEI)-DNA nanoparticles for enhanced gene delivery and expression in alveolar epithelial cells.

Enhancing gene delivery and expression in alveolar epithelial cells could offer the opportunity for the treatment of acquired and inherited lung diseases. Here, we show that particle adsorption of human insulin (INS) is capable of increasing plasmid DNA (pDNA) delivery from polyethylenimine (PEI) nanoparticles specifically in alveolar epithelial cells. INS receptors were predominantly detected on alveolar but not on bronchial epithelial cells.

Targeting of the beta(2)-adrenoceptor increases nonviral gene delivery to pulmonary epithelial cells in vitro and lungs in vivo.

Coupling of targeting ligands to polyethylenimine (PEI) has been previously used to improve transfection efficiency of PEI gene vectors. Here, we show that the beta(2)-adrenoceptor (beta(2)-AR) agonist, clenbuterol (Clen), can be used to improve gene transfer efficiency of PEI gene vectors on alveolar epithelial cells in vitro and in the lungs of mice in vivo. Clenbuterol conjugated to fluorescein-labeled bovine serum albumin resulted in clenbuterol-specific cellular uptake predominantly into alveolar but not bronchial epithelial cells.

Transgene expression of transfected supercoiled plasmid DNA concatemers in mammalian cells.

Background: Supercoiled topology of transfected plasmid DNA (pDNA) is critical for transgene expression in mammalian cells. In the present study, we analysed transgene expression of transfected supercoiled pDNA concatemers.

Methods: Jurkat T cells were transfected with a supercoiled 4.

Cell type differences in activity of the Streptomyces bacteriophage phiC31 integrase.

Genomic integration by the Streptomyces bacteriophage C31 integrase is a promising tool for non-viral gene therapy of various genetic disorders. We investigated the C31 integrase recombination activity in T cell derived cell lines, primary T lymphocytes and CD34(+) haematopoietic stem cells in comparison to mesenchymal stem cells and cell lines derived from lung-, liver- and cervix-tissue. In T cell lines, enhanced long-term expression above control was observed only with high amounts of integrase mRNA.

Targeting of the glucocorticoid hormone receptor with plasmid DNA comprising glucocorticoid response elements improves nonviral gene transfer efficiency in the lungs of mice.

Background: It has been previously demonstrated that plasmid DNA transport into the nucleus could be increased by transcription factor binding. We chose the glucocorticoid responsive element (GRE) which binds to the glucocorticoid receptor (GR), a transcription factor which is shuttled into the nucleus upon ligand binding such as dexamethasone.

Methods: We cloned two, four, and eight repetitive sequences of the GRE into the reporter plasmid pEGFPLuc.

Characterization of lactoferrin as a targeting ligand for nonviral gene delivery to airway epithelial cells.

In this study lactoferrin (Lf) was investigated as a targeting ligand for receptor-mediated gene delivery to human bronchial epithelial cells. A high number of lactoferrin receptors (LfRs) were detected on bronchial epithelial (BEAS-2B), but not on alveolar epithelial (A549) cells by fluorescence microscopy and FACS measurements, suggesting potential targeting selectivity for bronchial epithelial cells. Molecular conjugates with ratios of Lf to branched polyethylenimine 25 kDa (PEI) ranging from 4:1 to 1:40 (mol/mol) were synthesized and analyzed for complexation of plasmid DNA (pDNA), transfection efficiency, and cytotoxicity.

Uronic acids functionalized polyethyleneimine (PEI)-polyethyleneglycol (PEG)-graft-copolymers as novel synthetic gene carriers.

In this study, we investigated galacturonic (GalAc)- and mannuronic (ManAc) acids as novel targeting ligands for receptor-mediated gene delivery. GalAc and ManAc were coupled to either polyethyleneimine (PEI) or PEI-polyethyleneglycol (PEG). Furthermore, lactobionic acid (LacAc), which comprises a GalAc-related carbohydrate ring, was coupled to each of the polymers through its open-chain gluconic acid moiety.