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concerted nicking of donor and chromosomal acceptor dna promotes homology-directed gene targeting in human cells.the exchange of genetic information between donor and acceptor dna molecules by homologous recombination (hr) depends on the cleavage of phosphodiester bonds. although double-stranded and single-stranded dna breaks (ssbs) have both been invoked as triggers of hr, until very recently the focus has been primarily on the former type of dna lesions mainly due to the paucity of ssb-based recombination models. here, to investigate the role of nicked dna molecules as hr-initiating substrates in human s ...201122189101
Epirubicin potentiates rAAV2/5-mediated TRAIL expression in fibroblast-like synoviocytes and augments the anti-arthritis effects of rAAV2/5-TRAIL.OBJECTIVE.: Synovial cells in rheumatoid synovium display abnormal proliferation, which leads to joint destruction. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has been described as a pro-apoptotic factor in fibroblast-like synoviocytes (FLSs). This study was undertaken to investigate the functions of recombinant adeno-associated virus (rAAV2/5)-TRAIL in FLSs and arthritic mice. METHODS.: Primary human FLSs were infected with rAAV2/5-TRAIL in the presence or absence of ...201122131069
AAV-Mediated Gene Transfer of Human X-Linked Inhibitor of Apoptosis Protects against Oxidative Cell Death in Human RPE Cells.Purpose. To determine whether human X-linked inhibitor of apoptosis (XIAP) enhances the survival of cultured human retinal pigment epithelial cells exposed to H(2)O(2). Methods. ARPE-19 cells were exposed to H(2)O(2) to induce oxidative cell death. Intracellular reactive oxygen species (ROS) were measured using 2',7'-dichlorofluorescein diacetate. MTT assay was performed to quantify mitochondrial stress. Cell apoptosis was determined by TUNEL assay. Human XIAP was delivered with bicistronic exp ...201122039248
normal collagen and bone production by gene-targeted human osteogenesis imperfecta ipscs.osteogenesis imperfecta (oi) is caused by dominant mutations in the type i collagen genes. in principle, the skeletal abnormalities of oi could be treated by transplantation of patient-specific, bone-forming cells that no longer express the mutant gene. here, we develop this approach by isolating mesenchymal cells from oi patients, inactivating their mutant collagen genes by adeno-associated virus (aav)-mediated gene targeting, and deriving induced pluripotent stem cells (ipscs) that were expand ...201122031238
Injection of AAV2-BMP2 and AAV2-TIMP1 into the nucleus pulposus slows the course of intervertebral disc degeneration in an in vivo rabbit model.BACKGROUND CONTEXT: Intervertebral disc degeneration (IDD) is a common cause of back pain. Patients who fail conservative management may face the morbidity of surgery. Alternative treatment modalities could have a significant impact on disease progression and patients' quality of life. PURPOSE: To determine if the injection of a virus vector carrying a therapeutic gene directly into the nucleus pulposus improves the course of IDD. STUDY DESIGN: Prospective randomized controlled animal study. MET ...201122023960
virus infection recognition and early innate responses to non-enveloped viral vectors.numerous human genetic and acquired diseases could be corrected or ameliorated if viruses are harnessed to safely and effectively deliver therapeutic genes to diseased cells and tissues in vivo. innate immune and inflammatory response represents one of the key stumbling blocks during the development of viral-based therapies. in this review, current data on the early innate immune responses to viruses and to the most commonly used gene therapy vectors (using adenovirus and adeno-associated virus) ...201021994609
Production of recombinant adeno-associated viral vectors and use in in vitro and in vivo administration.Adeno-associated virus is a nonpathogenic human virus that has been developed into a gene-delivery vector due to its high efficiency of infection for many different cell types and its ability to persist and lead to long-term gene expression. This unit describes efficient methods to generate high-titer, research-grade, adenovirus-free recombinant single-stranded and self-complementary adeno-associated virus in various serotypes, along with methods to quantify the viral vectors. Two detailed metho ...201121971848
novel random peptide libraries displayed on aav serotype 9 for selection of endothelial cell-directed gene transfer vectors.we have demonstrated the potential of random peptide libraries displayed on adeno-associated virus (aav)2 to select for aav2 vectors with improved efficiency for cell type-directed gene transfer. aav9, however, may have advantages over aav2 because of a lower prevalence of neutralizing antibodies in humans and more efficient gene transfer in vivo. here we provide evidence that random peptide libraries can be displayed on aav9 and can be utilized to select for aav9 capsids redirected to the cell ...201121956692
advancements in adeno-associated viral gene therapy approaches: exploring a new horizon.gene therapy is a promising new therapeutic strategy that has been explored in a wide variety of diseases, ranging from cancer to hemophilia, and ocular disorders to autoimmune diseases, among others. proof of concept of gene transfer approaches has been shown in over 100 studies of animal models of disease, although only a few are under development for clinical application. the us food and drug administration and the european medicines agency have not approved any viral human gene therapy produ ...201121941595
development of the hybrid sleeping beauty-baculovirus vector for sustained gene expression and cancer therapy.antiangiogenesis is an appealing anticancer approach but requires continued presence of the antiangiogenic agents, which can be remedied by gene therapy. baculovirus is an emerging gene delivery vector but only mediates transient expression (<7 days); thus, this study primarily aimed to develop a hybrid baculovirus for sustained antiangiogenic gene expression and cancer therapy. we first constructed plasmids featuring adeno-associated virus inverted terminal repeats (aav itrs), orip/epstein-barr ...201121918552
Differential virus restriction patterns of rhesus macaque and human APOBEC3A: implications for lentivirus evolution.The human apolipoprotein B mRNA editing enzyme catalytic peptide-like 3 (APOBEC3; A3) family of proteins (A3A-H) are known to restrict various retroviruses and retroelements, but the full complement of rhesus macaque A3 proteins remains unclear. We report the isolation and characterization of the hA3A homologue from rhesus macaques (rhA3A) and show that the rhesus macaque and human A3 genes are orthologous. RhA3A is expressed at high levels in activated CD4+ T cells, is widely expressed in macaq ...201121868050
computationally designed adeno-associated virus (aav) rep 78 is efficiently maintained within an adenovirus vector.adeno-associated virus (aav) is a single-stranded parvovirus retaining the unique capacity for site-specific integration into a transcriptionally silent region of the human genome, a characteristic requiring the functional properties of the rep 78/68 polypeptide in conjunction with aav terminal repeat integrating elements. previous strategies designed to assemble these genetic elements into adenoviral (ad) backbones have been limited by the general intolerability of aav rep sequences, prompting ...201121844368
magnetically enhanced adeno-associated viral vector delivery for human neural stem cell infection.gene therapy technology is a powerful tool to elucidate the molecular cues that precisely regulate stem cell fates, but developing safe vehicles or mechanisms that are capable of delivering genes to stem cells with high efficiency remains a challenge. in this study, we developed a magnetically guided adeno-associated virus (aav) delivery system for gene delivery to human neural stem cells (hnscs). magnetically guided aav delivery resulted in rapid accumulation of vectors on target cells followed ...201121840595
site-specific integration by the adeno-associated virus rep protein.inserting genetic information at precise locations into the human genome has been the goal of gene transfer technology for almost two decades. the spectacular progress of mammalian genetics in the last two decades has led to the development of technology for genome editing and homologous recombination in human somatic cells that is finally approaching efficiency compatible with clinical application. site-specific integration, or the insertion of genes at known locations by enzymes with target re ...201121827397
cardiac aav9-s100a1 gene therapy rescues post-ischemic heart failure in a preclinical large animal model.as a prerequisite for clinical application, we determined the long-term therapeutic effectiveness and safety of adeno-associated virus (aav)-s100a1 gene therapy in a preclinical large animal model of heart failure. s100a1, a positive inotropic regulator of myocardial contractility, becomes depleted in failing cardiomyocytes in humans and animals, and myocardial-targeted s100a1 gene transfer rescues cardiac contractile function by restoring sarcoplasmic reticulum calcium (ca(2+)) handling in acut ...201121775667
electrospun nanofibrous scaffolds for controlled release of adeno-associated viral vectors.the integration of viral gene delivery with key features of biomaterial scaffolds that modulate viral delivery in a controlled manner offers a promising strategy for numerous tissue engineering applications. in this study adeno-associated virus (aav), which is widely utilized in human gene therapy as a gene carrier due to its safety and efficient gene delivery capability, was encapsulated within electrospun nanofibrous scaffolds composed of blended mixtures of elastin-like polypeptides (elp) and ...201121745607
hepatorenal correction in murine glycogen storage disease type i with a double-stranded adeno-associated virus vector.glycogen storage disease type ia (gsd-ia) is caused by the deficiency of glucose-6-phosphatase (g6pase). long-term complications of gsd-ia include life-threatening hypoglycemia and proteinuria progressing to renal failure. a double-stranded (ds) adeno-associated virus serotype 2 (aav2) vector encoding human g6pase was pseudotyped with four serotypes, aav2, aav7, aav8, and aav9, and we evaluated efficacy in 12-day-old g6pase (-/-) mice. hypoglycemia during fasting (plasma glucose <100-ámg/dl) was ...201121730973
dosage thresholds for aav2 and aav8 photoreceptor gene therapy in monkey.gene therapy is emerging as a therapeutic modality for treating disorders of the retina. photoreceptor cells are the primary cell type affected in many inherited diseases of retinal degeneration. successfully treating these diseases with gene therapy requires the identification of efficient and safe targeting vectors that can transduce photoreceptor cells. one serotype of adeno-associated virus, aav2, has been used successfully in clinical trials to treat a form of congenital blindness that requ ...201121697530
enhanced sialic acid-dependent endocytosis explains the increased efficiency of infection of airway epithelia by a novel adeno-associated virus.we previously used directed evolution in human airway epithelia to create adeno-associated virus 2.5t (aav2.5t), a highly infectious chimera of aav2 and aav5 with one point mutation (a581t). we hypothesized that the mechanism for its increased infection may be a higher binding affinity to the surface of airway epithelia than its parent aav5. here, we show that, like aav5, aav2.5t, uses 2,3n-linked sialic acid as its primary receptor; however, aav2.5t binds to the apical surface of human airway e ...201121697483
duchenne muscular dystrophy gene therapy: lost in translation?a milestone of molecular medicine is the identification of dystrophin gene mutation as the cause of duchenne muscular dystrophy (dmd). over the last 2 decades, major advances in dystrophin biology and gene delivery technology have created an opportunity to treat dmd with gene therapy. remarkable success has been achieved in treating dystrophic mice. several gene therapy strategies, including plasmid transfer, exon skipping, and adeno-associated virus-mediated microdystrophin therapy, have entere ...201121691429
an universal real-time pcr for the detection and quantification of adeno-associated virus serotype 2 derived inverted terminal repeat sequences.viral vectors based on different naturally occurring adeno-associated virus (aav) serotypes belong to the most promising tools in human gene therapy. for the production of recombinant aav (raav) vectors, researchers are focusing predominantly on cross-packaging an artificial aav genome based on serotype 2 (aav2) into the capsids derived from other serotypes. within the packaged genome the inverted terminal repeats (itrs) are the only cis-acting viral elements required for raav vector generation ...201121644816
aav2-mediated subretinal gene transfer of hifn-α attenuates experimental autoimmune uveoretinitis in mice.recent reports show that gene therapy may provide a long-term, safe and effective intervention for human diseases. in this study, we investigated the effectiveness of adeno-associated virus 2 (aav2) based human interferon-alpha (hifn-α) gene therapy in experimental autoimmune uveoretinitis (eau), a classic model for human uveitis.201121611186
direct comparison of four adeno-associated virus serotypes in mediating the production of antiangiogenic proteins in mouse muscle.to determine the adeno-associated virus (aav) serotype that most efficiently mediates muscle expression of antiangiogenic proteins, we injected four different serotype (1, 2, 7, and 8) aav vectors encoding mouse endostatin (mend) or human soluble flk-1 (hsflk-1) into a quadriceps muscle of c57bl/6 mice. the highest plasma levels of therapeutic protein were observed in aav8-injected mice (8 > 7 > 1 > 2). sustained expression of mend was detected for 6 months, whereas concentrations of hsflk-1 dec ...201121599511
vector characterization methods for quality control testing of recombinant adeno-associated viruses.adeno-associated virus (aav)-based vectors expressing therapeutic gene products have shown great promise for human gene therapy. a major challenge for translation of promising research to clinical development is the establishment of appropriate quality control (qc) test methods to characterize clinical grade aav vectors. this chapter focuses on qc testing, providing an overview of characterization methods appropriate for clinical vectors prepared for early phase clinical studies, and detailed de ...201121590401
effect of soluble icam-1 on a sjögren's syndrome-like phenotype in nod mice is disease stage dependent.intercellular adhesion molecule-1 (icam-1) is involved in migration and co-stimulation of t and b cells. membrane bound icam-1 is over expressed in the salivary glands (sg) of sjögren's syndrome (ss) patients and has therefore been proposed as a potential therapeutic target. to test the utility of icam-1 as a therapeutic target, we used local gene therapy in non obese diabetic (nod) mice to express soluble (s)icam-1 to compete with membrane bound icam-1 for binding with its receptor. therapy was ...201121589878
capsid-specific t-cell responses to natural infections with adeno-associated viruses in humans differ from those of nonhuman primates.hepatic adeno-associated virus serotype 2 (aav2)-mediated gene transfer failed to achieve sustained transgene product expression in human subjects. we formulated the hypothesis that rejection of aav-transduced hepatocytes is caused by aav capsid-specific cd8(+) t cells that become reactivated upon gene transfer. although this hypothesis was compatible with clinical data, which showed a rise in circulating aav capsid-specific t cells following injection of aav vectors, it did not explain that aav ...201121587208
adeno-associated virus-mediated human acidic fibroblast growth factor expression promotes functional recovery of spinal cord-contused rats.background: following spinal cord injury, delivery of neurotrophic factors to the injured spinal cord has been shown to promote axonal regeneration and functional recovery. in previous studies, we showed that acidic fibroblast growth factor (afgf) is a potent neurotrophic factor that promotes the regeneration of axotomized spinal cord or dorsal root ganglion neurons. methods: we constructed a recombinant adeno-associated virus (aav) vector to express human afgf and evaluated afgf expression and ...201121557400
a non membrane-targeted human soluble cd59 attenuates choroidal neovascularization in a model of age related macular degeneration.age related macular degeneration (amd) is the most common cause of blindness amongst the elderly. approximately 10% of amd patients suffer from an advanced form of amd characterized by choroidal neovascularization (cnv). recent evidence implicates a significant role for complement in the pathogenesis of amd. activation of complement terminates in the incorporation of the membrane attack complex (mac) in biological membranes and subsequent cell lysis. elevated levels of mac have been documented o ...201121552568
aav mediated gdnf secretion from retinal glia slows down retinal degeneration in a rat model of retinitis pigmentosa.mutations in over 80 identified genes can induce apoptosis in photoreceptors, resulting in blindness with a prevalence of 1 in 3,000 individuals. this broad genetic heterogeneity of disease impacting a wide range of photoreceptor functions renders the design of gene-specific therapies for photoreceptor degeneration impractical and necessitates the development of mutation-independent treatments to slow photoreceptor cell death. one promising strategy for photoreceptor neuroprotection is neurotrop ...201121522134
preclinical differences of intravascular aav9 delivery to neurons and glia: a comparative study of adult mice and nonhuman primates.other labs have previously reported the ability of adeno-associated virus serotype 9 (aav9) to cross the blood-brain barrier (bbb). in this report, we carefully characterized variables that might affect aav9's efficiency for central nervous system (cns) transduction in adult mice, including dose, vehicle composition, mannitol coadministration, and use of single-stranded versus self-complementary aav. we report that aav9 is able to transduce approximately twice as many neurons as astrocytes acros ...201121487395
intravenous gene therapy with pim-1 via a cardiotropic viral vector halts the progression of diabetic cardiomyopathy through promotion of prosurvival signaling.rationale: studies in transgenic mice showed the key role of (pim-1) (proviral integration site for moloney murine leukemia virus-1) in the control of cardiomyocyte function and viability. objective: we investigated whether pim-1 represents a novel mechanistic target for the cure of diabetic cardiomyopathy, a steadily increasing cause of nonischemic heart failure. methods and results: in streptozotocin-induced type 1 diabetic mice, pim-1 protein levels declined during progression of cardiomyopat ...201121474815
preclinical evaluation of gene delivery methods for the treatment of loco-regional disease in breast cancer.preclinical results with various gene therapy strategies indicate significant potential for new cancer treatments. however, many therapeutics fail at clinical trial, often due to differences in tissue physiology between animal models and humans, and tumor phenotype variation. clinical data relevant to treatment strategies may be generated prior to clinical trial through experimentation using intact patient tissue ex vivo. we developed a novel tumor slice model culture system that is universally ...201121444371
adeno-associated virus serotype 2 mediated transduction and coexpression of the human apoai and sr-bi gene in hepg2 cells.cholesterol efflux is the first step in the reverse cholesterol transport (rct) pathway, removing excess cholesterol from tissues, including the arterial wall, thus preventing the development of atherosclerosis. adeno-associated virus (raav) has demonstrated significant promise as a dna-delivery vector to treat serious human diseases. in this study, we constructed recombinant adeno-associated viruses coexpressing apoai and sr-bi successfully, the double gene mrna and protein were both strongly e ...201121431865
metabolic activities and chondrogenic differentiation of human mesenchymal stem cells following recombinant adeno-associated virus-mediated gene transfer and overexpression of fibroblast growth factor 2.the genetic manipulation of bone marrow-derived mesenchymal stem cells (mscs) is an attractive approach to produce therapeutic platforms for settings that aim at restoring articular cartilage defects. here, we examined the effects of recombinant adeno-associated virus (raav)-mediated overexpression of human fibroblast growth factor 2 (hfgf-2), a mitogenic factor also known to influence msc differentiation, upon the proliferative and chondrogenic activities of human mscs (hmscs) in a three-dimens ...201121417714
generation of recombinant adeno-associated virus.adeno-associated virus (aav) was discovered about 30 yr ago as a contaminant of adenovirus preparations. since its discovery, researchers have described many unique characteristics of aav biology that have made it attractive as a potential vector for gene therapy. for example, aav is not pathogenic, approx 80% of adults in the united states are seropositive, but in no case has the virus been implicated as the etiological agent for a human disease. aav is a defective parvovirus with a single-stra ...200121394584
[post-translational ligation of split cftr severed before tmd2 and its chloride channel function].mutations of cystic fibrosis transmembrane conductance regulator (cftr) gene leads to cystic fibrosis, an autosomal recessive genetic disorder affecting a number of organs including the lung airways, pancreas and sweat glands. in order to investigate the post-translational ligation of cftr with reconstructed functional chloride ion channel and the split ssp dnab intein-mediated protein trans-splicing was explored to co-deliver cftr gene into eukaryotic cells with two vectors. the human cftr cdna ...201021387835
[post-translational ligation and function of dual-vector transferred split cftr gene].the mutation of cystic fibrosis transmembrane conductance regulator (cftr) gene leads to an autosomal recessive genetic disorder cystic fibrosis (cf). the gene therapy for cf using adeno-associated virus (aav) vectors delivering cftr gene is restricted by the contents limitation of aav vectors. in this study the split cftr genes severed at its regulatory domain were delivered by a dual-vector system with an intein-mediated protein trans-splicing as a technique to investigate the post-translation ...201021351451
safe and effective gene transfer by adeno-associated virus of neonatal thymus-derived mesenchymal stromal cells.recently, human neonatal thymus-derived mesenchymal stromal cells (ntmscs) have been recognized as a promising mesenchymal stem cell source for combined cell and gene therapy. while efficient gene transfer is crucial for optimizing therapeutic efficacy, almost no studies have yet reported on the characteristics of ntmsc in terms of genetic modification. the present study investigates and realizes the potential of self-complementary adeno-associated viruses (scaavs) as an effective transduction t ...201121310455
synergistic antitumor effect of aav-mediated trail expression combined with cisplatin on head and neck squamous cell carcinoma. 201121291526
cystic fibrosis transmembrane conductance regulator with a shortened r domain rescues the intestinal phenotype of cftr-/- mice.gene transfer could provide a novel therapeutic approach for cystic fibrosis (cf), and adeno-associated virus (aav) is a promising vector. however, the packaging capacity of aav limits inclusion of the full-length cystic fibrosis transmembrane conductance regulator (cftr) cdna together with other regulatory and structural elements. to overcome aav size constraints, we recently developed a shortened cftr missing the n-terminal portion of the r domain (residues 708-759, cftr?r) and found that it r ...201121285372
effects of adeno-associated virus-2-mediated human bmp-7 gene transfection on the phenotype of nucleus pulposus cells.bone morphogenetic protein-7 (bmp-7) was found to stimulate the synthesis of proteoglycans (pgs) and collagen type ii. to increase the biological function of the nucleus pulposus (np) cells, the ad-hbmp-7 vector was also successfully constructed and transfected np cells. however, the disadvantages of adenovirus limit the usefulness of the ad-hbmp7 vector for clinical application. the raav2 vector has empirical advantages, especially for clinical use, to transfer exogenous genes into cells. the p ...201121246612
functional characterization of 58-kilodalton inhibitor of protein kinase in protecting against diabetic retinopathy via the endoplasmic reticulum stress pathway.58-kilodalton inhibitor of protein kinase (p58(ipk)) plays an important role in preventing endoplasmic reticulum (er) stress. it is an interferon-induced kinase that targets the eukaryotic translation initiation factor eukaryotic initiation factor 2 alpha. the aim of this study was to determine the roles of p58(ipk) in protecting against diabetic retinopathy (dr) by inhibiting er stress-signaling mediators.201121245960
systemic elimination of de novo capsid protein synthesis from replication-competent aav contamination in the liver.the capsid protein synthesis in targeted tissues resulting from residual contaminating replication-competent adeno-associated virus particles (rcaav) remains a concern for hazardous immune responses that shut down the factor ix expression in the hemophilia b clinical trial. to systematically reduce/eliminate the effects of potential contaminating rcaav particles, we designed a novel adeno-associated virus (aav) helper (ph22mir) with a microrna binding cassette containing multiple copies of liver ...201121244243
labeling and tracking human amniotic epithelial cells with green fluorescent protein in an adeno-associated virus vector.human amniotic epithelial cells (haecs) are a recently identified type of stem cell. thanks to their ready availability and the lower risk of teratoma formation, haecs have been studied and tested for a variety of human disease treatments and tissue reconstruction efforts. this aim of this study was to establish a stable tracking system to further monitor haecs in vivo after transplantation. haecs were isolated from the placentas of patients who visited the hunan province maternity and child car ...201121225467
an adeno-associated virus vector efficiently and specifically transduces mouse skeletal muscle.expression of a therapeutic gene in the skeletal muscle is a practical strategy to compensate a patients' insufficient circulating factor. its clinical application requires a muscle-targeting vector capable of inducing a continuous high-level transgene expression. we modified an adeno-associated virus serotype 2 (aav2) vector expressing luciferase from the mouse muscle creatine kinase gene promoter-enhancer (ckm). first, aavs1 insulator was inserted into the vector genome for transcriptional enh ...201121197588
characterization of anti-hiv activity mediated by r88-apobec3g mutant fusion proteins in cd4(+) t cells, peripheral blood mononuclear cells, and macrophages.abstract in this study, we characterized the anti-hiv activities of various r88-apobec3g (r88-a3g) mutant fusion proteins in which each a3g mutant was fused with a virus-targeting polypeptide (r14-88, hereafter named r88) derived from hiv-1 vpr. our results show that the introduction of the deaminase-defective mutant e259q into r88-a3g did not affect the virion incorporation of this mutant but blocked the protein's ability to inhibit hiv-1 infection. our data also reveal that the antiviral effec ...201121182427
gene therapy in ophthalmology: validation on cultured retinal cells and explants from postmortem human eyes.gene therapy studies in primates can provide important information regarding vector tropism, specific cellular expression, biodistribution, and safety prior to clinical trials. in this study, we report the assessment of transduction efficiency of recombinant adeno-associated virus (raav) vectors using human postmortem retina. transductions were performed using two in vitro models prepared from human tissue: dissociated cell cultures and retinal explants. these models were used to assess cellular ...201121142470
phenotypic correction of a mouse model for primary hyperoxaluria with adeno-associated virus gene transfer.primary hyperoxaluria type i (ph1) is an inborn error of metabolism caused by deficiency of the hepatic enzyme alanine-glyoxylate aminotransferase (agxt or agt) which leads to overproduction of oxalate by the liver and subsequent urolithiasis and renal failure. the current therapy largely depends on liver transplantation, which is associated with significant morbidity and mortality. to explore an alternative treatment, we used somatic gene transfer in a mouse genetic model for ph1 (agxt1ko). rec ...201021119625
intravenous scaav9 delivery of a codon-optimized smn1 sequence rescues sma mice.spinal muscular atrophy (sma) is the most common genetic disease leading to infant mortality. this neuromuscular disorder is caused by the loss or mutation of the telomeric copy of the 'survival of motor neuron' (smn) gene, termed smn1. loss of smn1 leads to reduced smn protein levels, inducing degeneration of motor neurons (mn) and progressive muscle weakness and atrophy. to date, sma remains incurable due to the lack of a method to deliver therapeutically active molecules to the spinal cord. g ...201021118896
treatment of atherosclerosis by transplantation of bone endothelial progenitor cells over-expressed paraoxonase-1 gene by recombinant adeno-associated virus in rat.endothelial dysfunction/loss is a key event in the development of vascular diseases, including native atherosclerosis (as). recent studies have shown that endothelial progenitor cells (epcs) have the ability to repair endothelial cells that have been lost or damaged following as. as a result, the therapy of transplanting epcs is a promising option for the treatment of as. however, the therapeutic effect on as with only epcs transplantation has not been satisfactory. the upregulation of those gen ...201021048304
the status of exon skipping as a therapeutic approach to duchenne muscular dystrophy.duchenne muscular dystrophy (dmd) is associated with mutations in the dystrophin gene that disrupt the open reading frame whereas the milder becker's form is associated with mutations which leave an in-frame mrna transcript that can be translated into a protein that includes the n- and c- terminal functional domains. it has been shown that by excluding specific exons at, or adjacent to, frame-shifting mutations, open reading frame can be restored to an out-of-frame mrna, leading to the productio ...201020978473
[study on time effect of gene expression of recombinant adeno-associated virus vector co-expressing human vascular endothelial growth factor 165 and human bone morphogenetic protein 7 genes].to study the time effect of the gene expression of recombinant adeno-associated virus (raav) vector co-expressing human vascular endothelial growth factor 165 (hvegf165) and human bone morphogenetic protein 7 (hbmp-7) genes so as to lay a theoretical foundation for gene therapy of osteonecrosis.201020939488
recombinant adeno-associated virus-mediated in utero gene transfer gives therapeutic transgene expression in the sheep.somatic in utero gene therapy aims to treat congenital diseases where pathology develops in perinatal life, thereby preventing permanent damage. the aim of this study was to determine whether delivery of self-complementary (sc) adeno-associated virus (aav) vector in utero would provide therapeutic long-term transgene expression in a large animal model. we performed ultrasound-guided intraperitoneal injection of scaav2/8-lp1-human factor ix (hfix)co (1 × 10(12) vector genomes/kg) in early (n = 4) ...201120919876
sustained enzymatic correction by raav-mediated liver gene therapy protects against induced motor neuropathy in acute porphyria mice.acute intermittent porphyria (aip) is characterized by a hereditary deficiency of hepatic porphobilinogen deaminase (pbgd) activity. clinical features are acute neurovisceral attacks accompanied by overproduction of porphyrin precursors in the liver. recurrent life-threatening attacks can be cured only by liver transplantation. we developed recombinant adeno-associated virus (raav) vectors expressing human pbgd protein driven by a liver-specific promoter to provide sustained protection against i ...201020877347
a naturally occurring human minidysferlin protein repairs sarcolemmal lesions in a mouse model of dysferlinopathy.dysferlinopathies are autosomal recessive, progressive muscle dystrophies caused by mutations in dysf, leading to a loss or a severe reduction of dysferlin, a key protein in sarcolemmal repair. currently, no etiological treatment is available for patients affected with dysferlinopathy. as for other muscular dystrophies, gene therapy approaches based on recombinant adeno-associated virus (raav) vectors are promising options. however, because dysferlin messenger rna is far above the natural packag ...201020861509
preclinical evaluation of a recombinant adeno-associated virus vector expressing human alpha-1 antitrypsin made using a recombinant herpes simplex virus production method.recombinant adeno-associated virus (raav) vectors offer promise for gene therapy of alpha-1 antitrypsin (aat) deficiency. a toxicology study in mice evaluated intramuscular injection of an raav vector expressing human aat (raav-cb-haat) produced using a herpes simplex virus (hsv) complementation system or a plasmid transfection (tfx) method at doses of 3 × 10(11) vg (1.2 × 10(13) vg/kg) for both vectors and 2 × 10(12) vg (8 × 10(13) vg/kg) for the hsv-produced vector. the hsv-produced vector had ...201120812844
preexisting immunity and low expression in primates highlight translational challenges for liver-directed aav8-mediated gene therapy.liver-directed gene therapy with adeno-associated virus (aav) vectors effectively treats mouse models of lysosomal storage diseases (lsds). we asked whether these results were likely to translate to patients. to understand to what extent preexisting anti-aav8 antibodies could impede aav8-mediated liver transduction in primates, commonly preexposed to aav, we quantified the effects of preexisting antibodies on liver transduction and subsequent transgene expression in mouse and nonhuman primate (n ...201020736932
redundant mechanisms for vascular growth factors in retinopathy of prematurity in vitro.current treatments for retinopathy of prematurity (rop) targeting single vascular growth factors are ineffective in preventing neoangiogenesis.201120720439
influence of specific blocking of the delta-like ligand 4/notch signal transduction pathway on the biological behavior of human umbilical vein endothelial cells.the influence of specific blocking of the delta-like ligand 4 (dll4)/notch signal transduction pathway on the biological behavior of human umbilical vein endothelial cells (huvecs) has been studied. recombinant adeno-associated virus (raav) vectors expressing an active small interfering rna (sirna) (vector 6) targeting the dll4 (raav-dll4-short hairpin rna [shrna]) was used to infect huvecs. the same cell line infected with empty plasmid (raav-egfp) was used as a control. stable transfection and ...201020701540
efficient transgene reconstitution with hybrid dual aav vectors carrying the minimized bridging sequences.a hybrid dual-vector system was developed recently as a universal platform to double the packaging capacity of recombinant adeno-associated virus (aav). in this system, the expression cassette is split into two independent aav vectors. a highly recombinogenic bridging dna sequence is engineered in both vectors to mediate target gene-independent homologous recombination between the split vector genomes. in the prototype hybrid vectors, a 0.87-kb dna fragment from the middle portion of the human p ...201120662564
comparative cardiac gene delivery of adeno-associated virus serotypes 1-9 reveals that aav6 mediates the most efficient transduction in mouse heart.cardiac gene transfer is an attractive tool for developing novel heart disease treatments. adeno-associated viral (aav) vectors are widely used to mediate transgene expression in animal models and are being evaluated for human gene therapy. however, it is not clear which serotype displays the best cardiac tropism. therefore, we curried out this study to directly compare aav serotypes 1-9 heart transduction efficiency after indirect intracoronary injection. aav-cytomegalovirus immediate early enh ...201020590676
liver-directed gene expression using recombinant aav 2/8 vectors--a tolerogenic strategy for gene delivery?vectors based on recombinant adeno-associated virus (aav) 2/8 hold considerable promise for use in human gene therapy. these vectors are safe, and have minimal immunostimulatory properties. their combination with efficient, liver-specific promoters allows high-level transgene expression in the hepatocytes of small and large animals. in small animal models, this high level of liver expression results in tolerance to the transgene products. tolerance to transgene products may also be achievable us ...201020587341
activation of the erk signaling pathway is involved in cd151-induced angiogenic effects on the formation of cd151-integrin complexes.to assess the roles of extracellular signal-regulated kinase (erk), p38, and cd151-integrin complexes on proliferation, migration, and tube formation activities of cd151-induced human umbilical vein endothelial cells (huvecs).201020581856
adeno-associated virus serotypes 7 and 8 outperform serotype 9 in expressing atheroprotective human apoe3 from mouse skeletal muscle.intramuscular injection of adeno-associated viral (aav) vectors is potentially a safe, minimally invasive procedure for the long-term gene expression of circulating antiatherogenic proteins. here, we compare secretion and atheroprotective effects of human apoe3 after injection of 3 pseudotyped aav vectors (aav2/7, aav2/8, or aav2/9), driven by the cmv enhancer/chicken β-actin (cag) promoter, into skeletal muscle of hyperlipidemic apolipoprotein e-deficient (apoe⁻/⁻) mice. vector viabilities were ...201120580777
real-time mr imaging with gadoteridol predicts distribution of transgenes after convection-enhanced delivery of aav2 vectors.gene therapies that utilize convention-enhanced delivery (ced) will require close monitoring of vector infusion in real time and accurate prediction of drug distribution. the magnetic resonance imaging (mri) contrast agent, gadoteridol (gd), was used to monitor ced infusion and to predict the expression pattern of glial cell line-derived neurotrophic factor (gdnf) protein after administration of adeno-associated virus type 2 (aav2) vector encoding human pre-pro-gdnf complementary dna. the nonhum ...201020551915
using a fed-batch culture strategy to enhance raav production in the baculovirus/insect cell system.recombinant adeno-associated virus (raav) is one of the most promising vectors for human gene therapy. however, the production systems that are currently available have a limited capacity and cannot provide sufficient quantities of raav for preclinical or clinical trials. many novel methods for improving raav production have been developed, but few researchers have focused on the culture process. in this study, we use a fed-batch culture system to enhance raav yield in the baculovirus/insect cel ...201020547323
[biological effects of recombinant adeno-associated virus 2 mediated human transforming growth factor beta1, encoding gene transfer to rabbit degenerative nucleus pulposus cells on proteoglycan level].to verify the potential of the recombinant adeno-associated virus 2 (raav2) vector as a strategy for human transforming growth factor beta1 (htgf-beta1) gene transfer in degenerative intervertebral discs of rabbit, to investigate the gene transduction efficacy and to quantify the biologic effects on the proteoglycan level after gene transferring.201020540272
eight years of clinical improvement in mptp-lesioned primates after gene therapy with aav2-haadc.this study completes the longest known in vivo monitoring of adeno-associated virus (aav)-mediated gene expression in nonhuman primate (nhp) brain. although six of the eight parkinsonian nhp originally on study have undergone postmortem analysis, as described previously, we monitored the remaining two animals for a total of 8 years. in this study, nhp received aav2-human l-amino acid decarboxylase (haadc) infusions into the mptp (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-lesioned putamen. re ...201020531394
[study on biological activity of recombinant adeno-associated virus vector co-expressing human vascular endothelial growth factor 165 and human bone morphogenetic protein 7 genes in vitro].to study the biological activity of recombinant adeno-associated virus vector (raav) co-expressing human vascular endothelial growth factor 165 (hvegf165) and human bone morphogenetic protein 7 (hbmp-7) genes in vitro so as to provide a new method for the therapeutics of osteonecrosis.201020459001
persistent expression of biologically active anti-her2 antibody by aavrh.10-mediated gene transfer.trastuzumab (herceptin) is a recombinant humanized monoclonal antibody (mab) directed against an extracellular region of the human epidermal growth-factor receptor type 2 (her2) protein. we hypothesized that a single adeno-associated virus (aav)-mediated genetic delivery of an anti-her2 antibody should be effective in mediating long-term production of anti-her2 and in suppressing the growth of human tumors in a xenograft model in nude mice. the adeno-associated virus gene transfer vector aavrh.1 ...201020448672
engineering of human pluripotent stem cells by aav-mediated gene targeting.precise genetic manipulation of human pluripotent stem cells will be required to realize their scientific and therapeutic potential. here, we show that adeno-associated virus (aav) gene targeting vectors can be used to genetically engineer human embryonic stem cells (escs) and induced pluripotent stem cells (ipscs). different types of sequence-specific changes, including the creation and correction of mutations, were introduced into the human hprt1 and hmga1 genes (hprt1 mutations being responsi ...201020407427
gene therapy rescues cone function in congenital achromatopsia.the successful restoration of visual function with recombinant adeno-associated virus (raav)-mediated gene replacement therapy in animals and humans with an inherited disease of the retinal pigment epithelium has ushered in a new era of retinal therapeutics. for many retinal disorders, however, targeting of therapeutic vectors to mutant rods and/or cones will be required. in this study, the primary cone photoreceptor disorder achromatopsia served as the ideal translational model to develop gene ...201020378608
raav9--a human-derived adeno-associated virus vector for efficient transgene expression in mouse cingulate cortex.the rostro-medial cortex of the mouse and rat, considered the functional homolog to the primate prefrontal cortex (pfc), is of growing importance for preclinical models of schizophrenia and other neurodevelopmental diseases for which symptoms typically emerge in adolescence and early adulthood. therefore, in order to explore molecular mechanisms operating during these critical stages of pfc development, it will be important to develop an efficient gene delivery system for the pfc of juvenile ani ...201020360371
cns-targeted gene therapy improves survival and motor function in a mouse model of spinal muscular atrophy.spinal muscular atrophy (sma) is a neuromuscular disease caused by a deficiency of survival motor neuron (smn) due to mutations in the smn1 gene. in this study, an adeno-associated virus (aav) vector expressing human smn (aav8-hsmn) was injected at birth into the cns of mice modeling sma. western blot analysis showed that these injections resulted in widespread expression of smn throughout the spinal cord, and this translated into robust improvement in skeletal muscle physiology, including incre ...201020234094
[large-scale production of recombinant adeno-associated virus (raav)].recombinant adeno-associated virus has been proven to be a promising gene delivery vector for human gene therapy with many advantages. successful applications of recombinant adeno-associated virus vectors in preclinical and clinical human gene therapies make it become a demanded product. a well-established and large-scale production system is therefore required. since wild type of adeno-associated virus was well characterized in 1989, progress has been made. particularly, package system of recom ...200920222456
frequent endonuclease cleavage at off-target locations in vivo.target-site dna breaks increase recombination frequencies, however, the specificity of the enzymes used to create them remains poorly defined. the location and frequency of off-target cleavage events are especially important when rare-cutting endonucleases are used in clinical settings. here, we identify noncanonical cleavage sites of i-scei that are frequently cut in the human genome by localizing adeno-associated virus (aav) vector-chromosome junctions, demonstrating the importance of in vivo ...201020216527
adeno-associated virus-mediated delivery of kringle 5 of human plasminogen inhibits orthotopic growth of ovarian cancer.kringle 5 (k5) of human plasminogen is a potent angiogenesis inhibitor. in this study, we investigated the effects of recombinant adeno-associated virus (aav)-mediated delivery of k5 in mouse models of human ovarian cancer. a single intramuscular injection of aav-k5 resulted in sustained expression of k5 reaching a maximum serum level of 800 ng ml(-1). gene therapy inhibited both vascular endothelial growth factor (vegf)-induced and tumor cell-induced angiogenesis in matrigel plug assays. furthe ...201020200565
ku regulates the non-homologous end joining pathway choice of dna double-strand break repair in human somatic cells.the repair of dna double-strand breaks (dsbs) is critical for the maintenance of genomic integrity and viability for all organisms. mammals have evolved at least two genetically discrete ways to mediate dna dsb repair: homologous recombination (hr) and non-homologous end joining (nhej). in mammalian cells, most dsbs are preferentially repaired by nhej. recent work has demonstrated that nhej consists of at least two sub-pathways-the main ku heterodimer-dependent or "classic" nhej (c-nhej) pathway ...201020195511
efficient recovery of dysferlin deficiency by dual adeno-associated vector-mediated gene transfer.deficiency of the dysferlin protein presents as two major clinical phenotypes: limb-girdle muscular dystrophy type 2b and miyoshi myopathy. dysferlin is known to participate in membrane repair, providing a potential hypothesis to the underlying pathophysiology of these diseases. the size of the dysferlin cdna prevents its direct incorporation into an adeno-associated virus (aav) vector for therapeutic gene transfer into muscle. to bypass this limitation, we split the dysferlin cdna at the exon 2 ...201020154340
nf-kappab activation mediates resistance to ifn beta in mll-rearranged acute lymphoblastic leukemia.acute lymphoblastic leukemia (all) harboring the t(4;11) translocation is associated with a very poor prognosis; innovative treatment strategies are required to improve the current 5-year survival rate of 30-40%. interferon beta (ifn beta) has shown promise in the treatment of both solid and hematologic malignancies, although the short half-life and toxicity associated with high doses have limited its clinical utility. to overcome these limitations, we investigated the effect of continuous, gene ...201020130599
fate of recombinant adeno-associated viral vector genomes during dna double-strand break-induced gene targeting in human cells.recombinant vectors based on adeno-associated virus (raav) are promising tools to specifically alter complex genomes through homologous recombination (hr)-based gene targeting. in a therapeutic setting, an aav donor vector will recombine with a mutant target locus in order to correct the mutation directly in the genome. the low frequency of hr in mammalian cells can be significantly improved by insertion of a dna double-strand break (dsb) into the target locus through expression of a site-specif ...201020021219
adeno-associated virus harboring fusion gene nt4-ant-shepherdin induce cell death in human lung cancer cells.to further enhance anticancer effect of shepherdin and overcome limitation of peptide therapy, recombinant adeno-associated virus (raav) was constructed with following strategies: therapeutic peptide secretory expression and adeno-associated virus gene transfer system. mtt assay and flow cytometric analysis revealed that raav harboring fusion gene nt4-ant-shepherdin significantly suppressed a549 cell growth in a time-dependent manner and induced apoptosis. in the infected a549 cells, survivin ex ...201019968500
adeno-associated virus small rep proteins are modified with at least two types of polyubiquitination.adeno-associated virus (aav) type 2 and 5 proteins rep52 and rep40 were polyubiquitinated during aav-adenovirus type 5 (ad5) coinfection and during transient transfection in either the presence or absence of ad5 e4orf6 and e1b-55k. polyubiquitination of small rep proteins via lysine 48 (k48) linkages, normally associated with targeting of proteins for proteasomal degradation, was detected only in the presence of e4orf6. the small rep proteins were ubiquitinated via lysine 63 (k63) following tran ...201019889761
dual reporter comparative indexing of raav pseudotyped vectors in chimpanzee airway.selecting the most efficient recombinant adeno-associated virus (raav) serotype for airway gene therapy has been difficult due to cross-specific differences in tropism and immune response between humans and animal models. chimpanzees--the closest surviving genetic relative of humans--provide a valuable opportunity to select the most effective serotypes for clinical trials in humans. however, designing informative experiments using this protected species is challenging due to limited availability ...201019826405
adeno-associated virus-mediated rhodopsin replacement provides therapeutic benefit in mice with a targeted disruption of the rhodopsin gene.the rhodopsin gene (rho) encodes a highly expressed g protein-coupled receptor that is central to visual transduction in rod photoreceptors. a suite of recombinant 2/5 adeno-associated viral (aav) rho replacement vectors has been generated in an attempt to recapitulate endogenous rhodopsin levels from exogenously delivered aav vectors in the retina of mice with a targeted disruption in the rhodopsin gene (rho(-/-) mice). approximately 40% of wild-type mouse rhodopsin mrna levels (rna taken from ...201019824806
rna interference inhibitors of hepatitis b virus.previously, we showed that short hairpin rnas (shrnas) targeting hepatitis b virus (hbv) potently inhibit the virus in a transient mouse model. however, subsequent studies showed that expression of these hairpins (as well as hairpins targeting human alpha-1 antitrypsin) from adeno-associated virus vectors (aav) cause fatality in mice. we used rational design to develop significantly more potent second-generation hbv rnai triggers embedded within the endogenous microrna (mirna) mir-30. a statisti ...200919796073
effects of structural variations of apobec3a and apobec3b genes in chronic hepatitis b virus infection.aim: human apobec3 deaminases induce g to a hypermutation in nascent dna strand of hepatitis b virus (hbv) genomes and seem to operate as part of the innate antiviral immune system. we analyzed the importance of apobec3a (a3a) and apobec3b (a3b) proteins, which are potent inhibitors of adeno-associated-virus and long terminal repeat (ltr)-retrotransposons, in chronic hbv infection. methods: we focused on the common deletion polymorphism that spans from the 3' part of a3a gene to the 3' portion o ...200919788695
[neuroprotective effect of raav-mediated rhbdnf gene transfection on rabbit retina against acute high intraocular pressure].to investigate the neuroprotective effect of human brain-derived neurotrophic factor gene transfection into rabbit retina against acute high intraocular pressure (hiop).200919778786
gene therapy with a promoter targeting both rods and cones rescues retinal degeneration caused by aipl1 mutations.aryl hydrocarbon receptor-interacting protein-like 1 (aipl1) is required for the biosynthesis of photoreceptor phosphodiesterase (pde). gene defects in aipl1 cause a heterogeneous set of conditions ranging from leber's congenital amaurosis (lca), the severest form of early-onset retinal degeneration, to milder forms such as retinitis pigmentosa (rp) and cone-rod dystrophy. in mice, null and hypomorphic alleles cause retinal degeneration similar to human lca and rp, respectively. thus these mouse ...201019710705
gene targeting in human pluripotent stem cells with adeno-associated virus vectors.human pluripotent stem cells, such as embryonic stem cells (hescs) and induced pluripotent stem cells (hipscs), have the ability to differentiate into various cell types, and will become a potential source of cellular materials for regenerative medicine. to make full use of hescs or hipscs for both basic and clinical research, genetic modification, especially gene targeting via homologous recombination (hr), would be an essential technique. this report describes the successful gene targeting of ...200919695233
immunomodulatory gene therapy prevents antibody formation and lethal hypersensitivity reactions in murine pompe disease.infantile pompe disease progresses to a lethal cardiomyopathy in absence of effective treatment. enzyme-replacement therapy (ert) with recombinant human acid alpha-glucosidase (rhgaa) has been effective in most patients with pompe disease, but efficacy was reduced by high-titer antibody responses. immunomodulatory gene therapy with a low dose adeno-associated virus (aav) vector (2 x 10(10) particles) containing a liver-specific regulatory cassette significantly lowered immunoglobin g (igg), igg1 ...201019690517
recombinant adeno-associated virus-mediated human kallikrein gene therapy protects against hypertensive target organ injuries through inhibiting cell apoptosis.overexpression of human tissue kallikrein (hk), mediated by recombinant adeno-associated virus (raav), decreased blood pressure in spontaneous hypertensive rats (shrs) and reduced injury to the heart, aorta and kidney. in this study, we used both an in vivo animal model and in vitro cell culture system to investigate whether raav-mediated hk gene therapy protects against organ damage by inhibiting cell apoptosis.200919684610
macrophage reverse cholesterol transport in mice expressing apoa-i milano.to compare the abilities of human wild-type apoa-i (wt apoa-i) and human apoa-i(milano) (apoa-i(m)) to promote macrophage reverse cholesterol transport (rct) in apoa-i-null mice infected with adeno-associated virus (aav) expressing either wt apoa-i or apoa-i(m).200919661486
stimulation of homology-directed gene targeting at an endogenous human locus by a nicking endonuclease.homologous recombination (hr) is a highly accurate mechanism of dna repair that can be exploited for homology-directed gene targeting. since in most cell types hr occurs very infrequently (approximately 10(-6) to 10(-8)), its practical application has been largely restricted to specific experimental systems that allow selection of the few cells that become genetically modified. hr-mediated gene targeting has nonetheless revolutionized genetics by greatly facilitating the analysis of mammalian ge ...200919651880
adeno-associated virus-delivered short hairpin-structured rna for androgen receptor gene silencing induces tumor eradication of prostate cancer xenografts in nude mice: a preclinical study.the androgen receptor (ar) is the most critical factor in prostate cancer progression. we previously demonstrated that silencing the ar using 2 unique small interfering rnas (no. 8 and no. 31 ar sirna) induces apoptotic cell death in ar-positive prostate cancer cells. to develop this ar sirna technique into a therapy for prostate cancers, we generated an adeno-associated virus (aav) vector to stably express a short hairpin-structured rna (shrna) against the ar gene in vivo. in addition to the no ...201019642108
sarcolemmal fragility secondary to the degradation of dystrophin in dilated cardiomyopathy, as estimated by electron microscopy.a common gene deletion or mutation of delta-sarcoglycan (delta-sg) in dystrophin-related proteins (drps) is identified in both to-2 strain hamsters and human families with dilated cardiomyopathy. we have succeeded in the long-lasting in vivo supplementation of a normal delta-sg gene by recombinant adeno-associated virus vector, restoration of the morphological and functional degeneration, and improvement in the prognosis of the to-2 hamster. to evaluate the integrity of the sarcolemma (sl) and t ...200319641652
[adeno-associated virus mediated t-bet gene transfer into sgc-7901 cell to regulate ifn-gamma production].in order to investigate the effect of t-bet on malignant cells, we selected sgc-7901, a kind of human gastric carcinoma cell line, and used gene clone technique and adeno-associated virus (aav) packing technology, thus obtaining a recombinant raav-egfp-t-bet and t-bet gene-transfected sgc-7901 cells. then the function of t-bet gene-infected sgc-7901 cells was researched by detecting the levels of ifn-gamma and t-bet production. the results showed: (1) it was verified that raav-t-bet's packing wa ...200919634682
directed evolution of adeno-associated virus for glioma cell transduction.glioblastoma multiforme (gbm) is a serious form of brain cancer for which there is currently no effective treatment. alternative strategies such as adeno-associated virus (aav) vector mediated-genetic modification of brain tumor cells with genes encoding anti-tumor proteins have shown promising results in preclinical models of gbm, although the transduction efficiency of these tumors is often low. as higher transduction efficiency of tumor cells should lead to enhanced therapeutic efficacy, a me ...201019618115
the tlr9-myd88 pathway is critical for adaptive immune responses to adeno-associated virus gene therapy vectors in mice.recombinant adeno-associated viruses (aavs) have been used widely for in vivo gene therapy. however, adaptive immune responses to aav have posed a significant hurdle in clinical application of aav vectors. recent advances have suggested a crucial role for innate immunity in shaping adaptive immune responses. how aav activates innate immunity, and thereby promotes aav-targeted adaptive immune responses, remains unknown. here we show that aav activates mouse plasmacytoid dcs (pdcs) via tlr9 to pro ...200919587448
persistent adeno-associated virus 2 and parvovirus b19 sequences in post-mortem human cerebellum.we previously reported in a large cohort (n = 104) of post-mortem tissues the detection of both the non-pathogenic adeno-associated virus (aav2) in approximately 13% and the pathogenic human parvovirus b19 (b19) in approximately 42% of human brains, particularly the dorsolateral prefrontal cortex. multiple animal parvoviruses target the developing cerebellum (cblm) resulting in hypoplasia and ataxia, but very little is known about the human parvoviruses and their ability to infect or cause disea ...200919585179
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