?url_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Adc&rft.relation=http%3A%2F%2Fd-scholarship-dev.library.pitt.edu%2F7003%2F&rft.title=EFFICIENT+AND+SELECTIVE+GENE+TRANSFER+DIRECTED+TO+MUSCLE+BY+TROPISM-MODIFIED+ADENO-ASSOCIATED+VIRUS+VECTOR&rft.creator=Yu%2C+Chi-Yi&rft.description=Gene+therapy+offers+a+promise+for+treating+inherited+muscle+disorders.+The+advantages+of+recombinant+adeno-associated+virus+(rAAV)+gene+delivery+vector+include+nonpathogenicity+and+long-term+gene+expression+after+a+single+administered+dose.+However%2C+rAAV+predominantly+transduces+the+liver+after+systemic+administration%2C+reducing+its+efficiency+for+gene+transfer+to+the+heart+and+skeletal+muscle.+The+question+of+how+to+deliver+the+therapeutic+genes+into+most+of+the+diseased+myofibers+becomes+a+challenge.+The+goal+of+this+project+is+to+develop+an+efficient+and+muscle-specific+AAV+vector+for+systemic+delivery.+Here%2C+the+muscle-targeting+peptide+ASSLNIA+was+incorporated+into+AAV2+capsid+after+residue+587+without+heparin-binding+motif+(587+TG+MTP+vector)+or+with+heparin-binding+motif+(588+HB+MTP+vector)+since+heparan+sulfate+is+the+primary+cellular+receptor+of+AAV2.+The+efficiencies+and+selectivities+of+muscle+targeting+of+modified+rAAVs+were+evaluated+in+vitro+and+in+vivo.+This+study+demonstrated+that+the+peptide-modified+vectors+maintained+their+myotube+transduction+ability.+Peptide-engineered+AAVs+decreased+their+transductions+in+non-muscle+cell+lines.+In+addition%2C+the+587+TG+MTP+vector+did+not+require+the+heparin-dependent+mechanism+for+muscular+targeting.+The+C2C12+myotube+transductions+of+587+TG+MTP+and+588+HB+MTP+vectors+were+inhibited+47%25~58%25+in+the+presence+of+free+ASSLNIA+peptide+while+unmodified+rAAV2+transduction+was+only+suppressed+by+25%25.+To+explore+the+muscle-targeting+abilities+of+modified+rAAVs+in+vivo%2C+mice+were+injected+intravenously+via+a+tail+vein+with+a+viral+dose+containing+9x10%5E11+genomic+particles.+After+four+weeks%2C+mouse+organs+were+harvested+for+the+luciferase+assay.+The+587+TG+MTP+vector+demonstrated+enhanced+muscle+and+heart+transduction+compared+to+unmodified+rAAV2.+Importantly%2C+the+587+TG+MTP+virus+significantly+reduced+its+transduction+of+liver%2C+lungs%2C+and+spleen.+The+vector+biodistribution+in+organs+was+also+determined+by+real-time+PCR+and+peptide-modified+vectors+showed+similar+targeting+effects.+Moreover%2C+this+study+found+that+both+587+TG+MTP+and+588+HB+MTP+vectors+were+resistant+to+antibody+neutralization.+These+results+indicate+that+this+muscle-targeting+peptide+facilitates+the+generation+of+an+efficient+and+muscle-specific+AAV+vector+for+systemic+gene+delivery+in+the+treatment+of+muscle+diseases+to+provide+clinical+and+public+health+benefits.&rft.date=2007-06-22&rft.type=University+of+Pittsburgh+ETD&rft.type=PeerReviewed&rft.format=application%2Fpdf&rft.language=en&rft.identifier=http%3A%2F%2Fd-scholarship-dev.library.pitt.edu%2F7003%2F1%2FYuCY2007.pdf&rft.identifier=++Yu%2C+Chi-Yi++(2007)+EFFICIENT+AND+SELECTIVE+GENE+TRANSFER+DIRECTED+TO+MUSCLE+BY+TROPISM-MODIFIED+ADENO-ASSOCIATED+VIRUS+VECTOR.++Doctoral+Dissertation%2C+University+of+Pittsburgh.++++(Unpublished)++