RESUMEN
Low efficiency, significant toxicity, polymer polydispersity and poorly understood delivery mechanisms have initially plagued the field of polymer-based gene therapy. Numerous strategies have helped to improve polyplexes, including the development of biodegradable polymers with reduced toxicity, incorporation of cell targeting, surface shielding and additional transport domains for effective and specific delivery, or improved chemistry for syntheses of polymers with uniform size and topology. Combined biooptical imaging and bioinformatics, providing insights into transfer bottlenecks, have helped to design improved polyplexes. Bioresponsive multifunctional polymers adapt in a dynamic manner to delivery barriers for efficient transfer of pDNA or siRNA to the target site.
Asunto(s)
Terapia Genética/tendencias , Polímeros , Animales , Biología Computacional , Sistemas de Liberación de Medicamentos , Marcación de Gen , Técnicas de Transferencia de Gen , Terapia Genética/métodos , Humanos , ARN Interferente PequeñoRESUMEN
We present an 11-year-old girl in whom high field strength MRI performed 2 1/2 years and 6 months before her death showed prominent hypointensity in the globus pallidus and substantia nigra consistent with iron deposition. This finding suggested Hallervorden-Spatz disease, which was confirmed at autopsy.
Asunto(s)
Enfermedades de los Ganglios Basales/patología , Encéfalo/patología , Imagen por Resonancia Magnética , Neurodegeneración Asociada a Pantotenato Quinasa/patología , Niño , Femenino , HumanosRESUMEN
A newly diagnosed 5-month-old infant with cystic fibrosis (CF) developed signs and symptoms of increased intracranial pressure (ICP) within days of starting pancreatic enzyme replacement therapy. Symptoms promptly resolved on two occasions after stopping enzyme replacement. At 10 months of age, enzyme replacement was well tolerated.
Asunto(s)
Fibrosis Quística/tratamiento farmacológico , Pancreatina/administración & dosificación , Seudotumor Cerebral/inducido químicamente , Fibrosis Quística/complicaciones , Fármacos Gastrointestinales/efectos adversos , Humanos , Lactante , Masculino , Pancreatina/efectos adversosRESUMEN
The epidermal growth factor receptor (EGFR) is upregulated within a high percentage of solid tumors and hence is an attractive target for tumor-targeted therapies including gene therapy. The natural EGFR ligand epidermal growth factor (EGF) has been used for this purpose, despite the risk of mitogenic effects due to EGFR activation. We have developed a fully synthetic, EGFR-targeted gene delivery system based on PEGylated linear polyethylenimine (LPEI), allowing evaluation of different EGFR-binding peptides in terms of transfection efficiency and EGFR activation. Peptide sequences directly derived from the human EGF molecule enhanced transfection efficiency with concomitant EGFR activation. Only the EGFR-binding peptide GE11, which has been identified by phage display technique, showed specific enhancement of transfection on EGFR-overexpressing tumor cells including glioblastoma and hepatoma, but without EGFR activation. EGFR targeting led to high levels of cell association of fluorescently labeled polyplexes after only 30 min of incubation. EGF pretreatment of cells induced enhanced cellular internalization of all polyplex types tested, pointing at generally enhanced macropinocytosis. EGF polyplexes diminished cell surface expression of EGFR for up to 4 hr, whereas GE11 polyplexes did not. In a clinically relevant orthotopic prostate cancer model, intratumorally injected GE11 polyplexes were superior in inducing transgene expression when compared with untargeted polyplexes.