| adeno-associated virus-mediated expression of β-hexosaminidase prevents neuronal loss in the sandhoff mouse brain. | sandhoff disease, a gm2 gangliosidosis caused by a deficiency in β-hexosaminidase, is characterized by progressive neurodegeneration. although loss of neurons in association with lysosomal storage of glycosphingolipids occurs in patients with this disease, the molecular pathways that lead to the accompanying neurological defects are unclear. using an authentic murine model of gm2 gangliosidosis, we examined the pattern of neuronal loss in the central nervous system and investigated the effects o ... | 2011 | 21852247 |
| NADPH oxidase 1-mediated oxidative stress leads to dopamine neuron death in Parkinson's disease. | Aim: Oxidative stress has long been considered as a major contributing factor in the pathogenesis of Parkinson's disease. However, molecular sources for reactive oxygen species in Parkinson's disease have not been clearly elucidated. Herein, we sought to investigate whether a superoxide- producing NADPH oxidases (NOXs) are implicated in oxidative stress-mediated dopaminergic neuronal degeneration . Results: Expression of various Nox isoforms and cytoplasmic components were investigated in N27, ... | 2011 | 22098189 |
| ATP7A Gene Addition to the Choroid Plexus Results in Long-term Rescue of the Lethal Copper Transport Defect in a Menkes Disease Mouse Model. | Menkes disease is a lethal infantile neurodegenerative disorder of copper metabolism caused by mutations in a P-type ATPase, ATP7A. Currently available treatment (daily subcutaneous copper injections) is not entirely effective in the majority of affected individuals. The mottled-brindled (mo-br) mouse recapitulates the Menkes phenotype, including abnormal copper transport to the brain owing to mutation in the murine homolog, Atp7a, and dies by 14 days of age. We documented that mo-br mice on C57 ... | 2011 | 21878905 |
| The Putative Metal Coordination Motif in the Endonuclease Domain of Human Parvovirus B19 NS1 Is Critical for NS1 Induced S Phase Arrest and DNA Damage. | The non-structural proteins (NS) of the parvovirus family are highly conserved multi-functional molecules that have been extensively characterized and shown to be integral to viral replication. Along with NTP-dependent helicase activity, these proteins carry within their sequences domains that allow them to bind DNA and act as nucleases in order to resolve the concatameric intermediates developed during viral replication. The parvovirus B19 NS1 protein contains sequence domains highly similar to ... | 2012 | 22211107 |
| Viral vectors for gene delivery to the central nervous system. | The potential benefits of gene therapy for neurological diseases such as Parkinson's, Amyotrophic Lateral Sclerosis (ALS), Epilepsy, and Alzheimer's are enormous. Even a delay in the onset of severe symptoms would be invaluable to patients suffering from these and other diseases. Significant effort has been placed in developing vectors capable of delivering therapeutic genes to the CNS in order to treat neurological disorders. At the forefront of potential vectors, viral systems have evolved to ... | 2011 | 22001604 |
| [recombinant adeno-associated virus vector related impurities]. | recombinant adeno-associated virus (raav)-based vectors that can stably express therapeutic genes in vivo without detectable side-effect have shown great promise for human gene therapy. a major challenge for translation of promising research to clinical development is how to establish clinically compatible purification methods in separating raav from potentially pathogenic impurities, especially raav vector-related impurities, a class of impurities corresponding to aav particles that closely res ... | 2011 | 21845838 |
| Absence of ocular malignant transformation after sub-retinal delivery of rAAV2/2 or integrating lentiviral vectors in p53-deficient mice. | Insertional mutagenesis following gene therapy with gammaretroviral vectors can cause the development of lymphoproliferation in children with X-linked severe combined immunodeficiency. In experimental studies, recombinant adeno-associated virus (rAAV) vectors have also been reported to increase susceptibility to carcinogenesis. The possibility of vector-induced transformation in quiescent ocular cells is probably significantly lower than in mitotically active cells, but given the increasing numb ... | 2011 | 22113317 |
| aav serotype 2/1-mediated gene delivery of anti-inflammatory interleukin-10 enhances neurogenesis and cognitive function in app+ps1 mice. | brain inflammation is a double-edged sword. it is required for brain repair in acute damage, whereas chronic inflammation and autoimmune disorders are neuropathogenic. certain proinflammatory cytokines and chemokines are closely related to cognitive dysfunction and neurodegeneration. representative anti-inflammatory cytokines, such as interleukin (il)-10, can suppress neuroinflammation and have significant therapeutic potentials in ameliorating neurodegenerative disorders such as alzheimer's dis ... | 2011 | 21918553 |
| Long-term functional adeno-associated virus-microdystrophin expression in the dystrophic CXMDj dog. | Duchenne muscular dystrophy (DMD) is a severe, inherited, muscle-wasting disorder caused by mutations in the dystrophin gene. Preclinical studies of adeno-associated virus gene therapy for DMD have been described in mouse and dog models of this disease. However, low and transient expression of microdystrophin in dystrophic dogs and a lack of long-term microdystrophin expression associated with a CD8(+) ?T-cell response in DMD patients suggests that the development of improved microdystrophin gen ... | 2011 | 22144143 |
| continuous cd8⁺ t-cell priming by dendritic cell cross-presentation of persistent antigen following adeno-associated virus-mediated gene delivery. | recombinant adeno-associated virus (raav) vectors establish persistent transgene expression in the skeletal muscle of mice. how dendritic cells acquire encoded antigens for cd8(+) t-cell priming is unknown. here we document cd8(+) t-cell priming after lethal irradiation and bone marrow reconstitution of mice treated with an aav vector several weeks earlier. temporal separation of vector delivery and successful class i antigen presentation indicated that t-cell priming does not necessarily requir ... | 2011 | 21880763 |
| Development and characterization of a novel rat model of Parkinson's disease induced by sequential intranigral administration of AAV-a-synuclein and the pesticide, rotenone. | Modeling Parkinson's disease remains a major challenge for preclinical researchers, as existing models fail to reliably recapitulate all of the classic features of the disease, namely, the progressive emergence of a bradykinetic motor syndrome with underlying nigrostriatal a-synuclein accumulation protein and nigrostriatal neurodegeneration. One limitation of the existing models is that they are normally induced by a single neuropathological insult, whereas the human disease is thought to be mul ... | 2011 | 22198020 |
| BAAV mediated GJB2 gene transfer restores gap junction coupling in cochlear organotypic cultures from deaf Cx26Sox10Cre mice. | The deafness locus DFNB1 contains GJB2, the gene encoding connexin26 and GJB6, encoding connexin30, which appear to be coordinately regulated in the inner ear. In this work, we investigated the expression and function of connexin26 and connexin30 from postnatal day 5 to adult age in double transgenic Cx26(Sox10Cre) mice, which we obtained by crossing connexin26 floxed mice with a deleter Sox10-Cre line. Cx26(Sox10Cre) mice presented with complete connexin26 ablation in the epithelial gap junctio ... | 2011 | 21876744 |
| liver production of sulfamidase reverses peripheral and ameliorates cns pathology in mucopolysaccharidosis iiia mice. | mucopolysaccharidosis type iiia (mpsiiia) is an inherited lysosomal storage disease caused by deficiency of sulfamidase, resulting in accumulation of the glycosaminoglycan (gag) heparan sulfate. it is characterized by severe progressive neurodegeneration, together with somatic alterations, which lead to death during adolescence. here, we tested the ability of adeno-associated virus (aav) vector-mediated genetic modification of either skeletal muscle or liver to revert the already established dis ... | 2011 | 22008915 |
| neuronal nogo-a upregulation does not contribute to er stress-associated apoptosis but participates in the regenerative response in the axotomized adult retina. | nogo-a, an axonal growth inhibitory protein known to be mostly present in cns myelin, was upregulated in retinal ganglion cells (rgcs) after optic nerve injury in adult mice. nogo-a increased concomitantly with the endoplasmic reticulum stress (er stress) marker c/ebp homologous protein (chop), but chop immunostaining and the apoptosis marker annexin v did not co-localize with nogo-a in individual rgc cell bodies, suggesting that injury-induced nogo-a upregulation is not involved in axotomy-indu ... | 2011 | 22193546 |
| Identification of Adeno-Associated Viral Vectors Suitable for Intestinal Gene Delivery and Modulation of Experimental Colitis. | Effective gene transfer with sustained gene expression is an important adjunct to the study of intestinal inflammation and future therapy in inflammatory bowel disease. Recombinant adeno-associated virus (AAV) vectors are ideal for gene transfer and long-term transgene expression. The purpose of our study was to identify optimal AAV pseudotypes for transduction of the epithelium in the small intestine and colon, which could be used for studies in experimental colitis. The tropism and transductio ... | 2011 | 22114116 |
| evaluation of the fate of raav genomes following in vivo administration. | recombinant adeno-associated virus (raav) vectors are capable of mediating long-term gene expression in a wide variety of animals, including primates. the raav genome is packaged into the virion as single-stranded dna devoid of any viral genes. a proportion of the single-stranded genomes are converted into transcriptionally active double-stranded dna (dsdna) early after nuclear entry by second-strand synthesis mediated by host repair dna polymerases or/and by annealing of the raav (-) and (+) st ... | 2011 | 22034033 |
| ENHANCED ATHLETIC PERFORMANCE UPON MULTI-SITE AAV-IGF1 GENE TRANSFER COINCIDES WITH MASSIVE MODIFICATION OF THE MUSCLE PROTEOME. | The recent progress in gene therapy has hinted at the potential misuse of gene transfer in sports to achieve better athletic performance, while escaping from traditional doping detection methods. Suitable animal models are therefore required in order to better define the potential effects and risks of gene doping. Here we describe a mouse model of gene doping based on the AAV-mediated delivery of the IGF-1 cDNA to multiple muscles. This treatment determined marked muscle hypertrophy, neovascular ... | 2011 | 22017471 |
| Adeno-associated virus activates an innate immune response in normal human cells but not in osteosarcoma cells. | Adeno-associated virus (AAV) is a small, DNA-containing dependovirus with promising potential as a gene delivery vehicle. Given the variety of applications of AAV-based vectors in the treatment of genetic disorders, numerous studies have focused on the immunogenicity of recombinant AAV. In general, AAV vectors appear not to induce strong inflammatory responses. We have found that AAV2, when it infects the osteosarcoma cells U2OS, can initiate part of its replicative cycle in the absence of helpe ... | 2011 | 21957288 |
| a simplified immune suppression scheme leads to persistent micro-dystrophin expression in duchenne muscular dystrophy dogs. | abstract highly abbreviated micro-dystrophin genes have been intensively studied for duchenne muscular dystrophy (dmd) gene therapy. following adeno-associated virus (aav) gene transfer, robust microgene expression is achieved in murine dmd models in the absence of immune suppression. interestingly, a recent study suggests that aav gene transfer in dystrophic dogs may require up to 18 weeks' immune suppression using a combination of three different immune-suppressive drugs (cyclosporine, mycop ... | 2011 | 21967249 |
| Antibody-based protection against HIV infection by vectored immunoprophylaxis. | Despite tremendous efforts, development of an effective vaccine against human immunodeficiency virus (HIV) has proved an elusive goal. Recently, however, numerous antibodies have been identified that are capable of neutralizing most circulating HIV strains. These antibodies all exhibit an unusually high level of somatic mutation, presumably owing to extensive affinity maturation over the course of continuous exposure to an evolving antigen. Although substantial effort has focused on the design o ... | 2011 | 22139420 |
| Humoral immunity to AAV-6, 8 and 9 in normal and dystrophic dogs. | AAV-6, 8 and 9 are promising gene delivery vectors for testing novel Duchenne muscular dystrophy gene therapy in the canine model. Humoral immunity greatly influences in vivo AAV transduction. However, neutralizing antibodies to AAV-6, 8 and 9 have not been systemically examined in normal and dystrophic dogs. To gain information on the seroprevalence of antibodies to AAV-6, 8 and 9, we measured neutralizing antibody titers in 72 naïve serum samples and 26 serum samples obtained from dogs that ... | 2011 | 22040468 |
| Ineffective CD8(+) T-cell immunity to adeno-associated virus can result in prolonged liver injury and fibrogenesis. | Chronic viral hepatitis depends on the inability of the T-cell immune response to eradicate antigen. This results in a sustained immune response accompanied by tissue injury and fibrogenesis. We have created a mouse model that reproduces these effects, based on the response of CD8(+) T cells to hepatocellular antigen delivered by an adeno-associated virus (AAV) vector. Ten thousand antigen-specific CD8(+) T cells undergo slow expansion in the liver and can precipitate a subacute inflammatory hep ... | 2011 | 21925469 |
| Adeno-associated virus-mediated local delivery of LIGHT suppresses tumorigenesis in a murine cervical cancer model. | LIGHT is a tumor necrosis factor superfamily ligand that is considered as a promising candidate for cancer therapy. It has a potent antitumor activity through establishing lymphoid-like tissues inside tumor sites and recruiting naive T cells into the tumor. In this study, we examined the possibility of antitumor activity by expressing LIGHT in cervical cancer (CC) model. A recombinant adeno-associated virus (AAV) vector was chosen for the transfer, based on its transfection efficiency and lack o ... | 2011 | 21904218 |
| genetic interleukin-10 deficiency causes vascular remodeling via the upregulation of nox1. | interleukin (il)-10 is an anti-inflammatory cytokine. nox1 is a mitogenic oxidase (p65-mox). the objective of this study was to test a hypothesis that il-10 deficiency would cause vascular remodeling via the upregulation of nox1. | 2011 | 21918473 |
| Fighting blindness with adeno-associated virus serotype 8. | | 2011 | 22044092 |
| Hypoxia-regulated retinal glial cell-specific promoter for potential gene therapy in disease. | Retinal Müller cells span the retina and secrete several trophic factors and represent the functional link between blood vessels and neurons, making them attractive targets for gene therapy. Therefore, a hypoxia-regulated, retinal glial cell-specific vector was constructed and tested for its response to hypoxia. | 2011 | 21960554 |
| sustained correction of otc deficiency in spf( ash) mice using optimized self-complementary aav2/8 vectors. | ornithine transcarbamylase deficiency (otcd) is the most common inborn error of urea synthesis. complete otcd can result in hyperammonemic coma in the neonatal period, which can rapidly become fatal. current acute therapy involves dialysis; chronic therapy involves the stimulation of alternate nitrogen clearance pathways; and the only curative approach is liver transplantation. adeno-associated virus (aav) vector-based gene therapy would add to current treatment options provided the vector deliv ... | 2011 | 21850052 |
| production and purification of recombinant adeno-associated vectors. | the use of recombinant adeno-associated virus (raav) vectors in gene therapy for preclinical studies in animal models and human clinical trials is increasing, as these vectors have been shown to be safe and to mediate persistent transgene expression in vivo. constant improvement in raav manufacturing processes (upstream production and downstream purification) has paralleled this evolution to meet the needs for larger vector batches, higher vector titer, and improved vector quality and safety. th ... | 2011 | 22034039 |
| anti-gp120 minibody gene transfer to female genital epithelial cells protects against hiv-1 virus challenge in vitro. | although cervico-vaginal epithelial cells of the female lower genital tract provide the initial defense system against hiv-1 infection, the protection is sometimes incomplete. thus, enhancing anti-hiv-1 humoral immunity at the mucosal cell surface by local expression of anti-hiv-1 broadly neutralizing antibodies (bnab) that block hiv-1 entry would provide an important new intervention that could slow the spread of hiv/aids. | 2011 | 22031835 |
| Bovine AAV transcytosis inhibition by tannic acid results in functional expression of CFTR in vitro and altered biodistribution in vivo. | Bovine adeno-associated virus (BAAV) can enter a cell either through a transcytosis or transduction pathway. We previously demonstrated that particles entering via the transcytosis pathway can be redirected to transduce the cell by blocking particle exocytosis with tannic acid (TA). To investigate whether this approach is useful in lung gene therapy applications, we tested the effect of TA on BAAV transduction in cystic fibrosis airway epithelia in vitro, and in mouse lung in vivo. Our findings ... | 2011 | 22011646 |
| The amino acid linker between the endonuclease and helicase domains of AAV5 Rep plays a critical role in DNA-dependent oligomerization. | The adeno-associated virus (AAV) genome encodes four Rep proteins, all of which contain an SF3 helicase domain. The larger Rep proteins, Rep78 and Rep68, are required for viral replication whereas Rep40 and Rep52 are needed to package AAV genomes into pre-formed capsids; these smaller proteins are missing the site-specific DNA binding and endonuclease domain found in Rep68/78. Other viral SF3 helicases such as the SV40 large T antigen and the papillomavirus E1 protein are active as hexameric ass ... | 2011 | 22205752 |
| 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) ... | 2010 | 21994609 |
| self-complementary adeno-associated viral vectors for gene therapy of hemophilia b: progress and challenges. | therapies currently used for hemophilia involve injection of protein concentrates that are expensive, invasive and associated with side effects such as development of neutralizing antibodies (inhibitors) that diminish therapeutic efficacy. gene transfer is an attractive alternative to circumvent these issues. however, until now, clinical trials using gene therapy to treat hemophilia have failed to demonstrate sustained efficacy, although a vector based on a self-complementary adeno-associated vi ... | 2011 | 21939421 |
| Continuous local delivery of interferon-ß stabilizes tumor vasculature in an orthotopic glioblastoma xenograft resection model. | High-grade glioblastomas have immature, leaky tumor blood vessels that impede the efficacy of adjuvant therapy. We assessed the ability of human interferon (hIFN)-ß delivered locally via gene transfer to effect vascular stabilization in an orthotopic model of glioblastoma xenograft resection. | 2011 | 21878236 |
| Novel Mini-Dystrophin Gene Dual Adeno-Associated Virus Vectors Restore Neuronal Nitric Oxide Synthase Expression at the Sarcolemma. | Abstract Six- to 8-kb mini-dystrophin genes are promising candidates for Duchenne muscular dystrophy (DMD) gene therapy. Several dual adeno-associated virus (AAV) mini-dystrophin vectors have been tested in dystrophin-deficient mice. Despite the encouraging preclinical results, none of the existing dual AAV vectors can restore sarcolemmal neuronal nitric oxide synthase (nNOS) expression. Localization of nNOS to the sarcolemma may greatly improve the therapeutic outcome in DMD (Lai, Y., Thomas, ... | 2011 | 21933029 |
| Detection of adeno-associated virus viremia in hematopoietic cell transplant recipients. | Adeno-associated virus (AAV) is widely considered to be nonpathogenic, but the clinical epidemiology of this virus is limited. By use of polymerase chain reaction assays, we investigated the incidence and clinical significance of AAV viremia in a population of consecutive recipients of a hematopoietic cell transplant (HCT). Four (2.8%) of 145 patients developed AAV viremia after HCT. Viremia was low level and transient in all patients. Two patients were admitted to the hospital and died in proxi ... | 2011 | 22006992 |
| AAV9 Transduction In The Central Nervous System Of Non-Human Primates. | Widespread distribution of gene products at clinically relevant levels throughout the central nervous system (CNS) has been challenging. Adeno-associated viral vector 9 (AAV9) has been reported as a good candidate for intravascular gene delivery, but low levels of pre-existing antibody titers against AAV in the blood abrogate cellular transduction within the CNS. In the present study we compared the effectiveness of vascular to cerebrospinal fluid (CSF) delivery of AAV9 in transducing CNS tissue ... | 2011 | 22201473 |
| The assessment of adeno-associated vectors as potential intrinsic treatments for brainstem axon regeneration. | BACKGROUND: Adeno-associated virus (AAV) vector mediated transgene expression is a promising therapeutic to change the intrinsic state of neurons and promote repair after CNS injury. Given that numerous transgenes have been identified as potential candidates, the present study demonstrates how to determine if their expression by AAV has a direct intrinsic effect on axon regeneration. METHODS: Serotype 2 AAV-EGFP was stereotaxically injected into the brainstem of adult rats, followed by a complet ... | 2011 | 22106053 |
| the assembly-activating protein promotes capsid assembly of different adeno-associated virus serotypes. | adeno-associated virus type 2 (aav2) capsid assembly requires the expression of a virally encoded assembly-activating protein (aap). by providing aap together with the capsid protein vp3, capsids are formed that are composed of vp3 only. electron cryomicroscopy analysis of assembled vp3-only capsids revealed all characteristics of the wild-type aav2 capsids. however, in contrast to capsids assembled from vp1, vp2, and vp3, the pores of vp3-only capsids were more restricted at the inside of the 5 ... | 2011 | 21917944 |
| Gene therapy in skeletal muscle mediated by adeno-associated virus vectors. | Adeno-associated virus (AAV) is the most promising gene delivery vehicle for muscle-directed gene therapy. AAV's natural tropism to muscle cells, long-term persistent transgene expression, multiple serotypes, as well as its minimal immune response have made AAV vectors well suited for muscle-directed gene therapy. AAV vector-mediated gene delivery to augment muscle structural proteins, such as dystrophin and sarcoglycans, offers great hope for muscular dystrophy patients. In addition, muscle can ... | 2011 | 22034028 |
| novel cytotoxic vectors based on adeno-associated virus. | vectors based on adeno-associated virus (aav) are promising tools for gene therapy. the production of strongly toxic vectors, for example for cancer-directed gene transfer, is often unfeasible due to uncontrolled expression of toxic genes in vector-producing cells. using an approach based on transcriptional repression, we have created novel aav vectors carrying the genes coding for diphtheria toxin a (dta) and the pro-apoptotic puma protein. the dta vector had a significant toxic effect on a pan ... | 2010 | 22069574 |
| Recombinant adeno-associated viral vector production and purification. | Gene delivery vectors based on recombinant adeno-associated virus (AAV) are powerful tools for studying myogenesis in normal and diseased conditions. Strategies have been developed to use AAV to increase, down-regulate, or modify expression of a particular muscle gene in a specific muscle, muscle group(s), or all muscles in the body. AAV-based muscle gene therapy has been shown to cure several inherited muscle diseases in animal models. Early clinical trials have also yielded promising results. ... | 2012 | 22130842 |
| In utero administration of Ad5 and AAV pseudotypes to the fetal brain leads to efficient, widespread and long-term gene expression. | The efficient delivery of genetic material to the developing fetal brain represents a powerful research tool and a means to supply therapy in a number of neonatal lethal neurological disorders. In this study, we have delivered vectors based upon adenovirus serotype 5 (Ad5) and adeno-associated virus (AAV) pseudotypes 2/5, 2/8 and 2/9 expressing green fluorescent protein to the E16 fetal mouse brain. One month post injection, widespread caudal to rostral transduction of neural cells was observed. ... | 2011 | 22071970 |
| tetradecanoylphorbol-13-acetate (tpa) significantly increases aav2/5 transduction of human neuronal cells in vitro. | recombinant adeno-associated virus type 2 (aav2) vectors have shown great promise in current ophthalmology clinical trials targeting gene delivery to the retinal pigment epithelium (rpe). to treat the majority of retinal diseases, however, gene delivery would need to be targeted to photoreceptor neurons of the outer retina. aav2 pseudotyped with the aav5 capsid (aav2/5) has shown far greater transduction efficiency in photoreceptors compared to standard aav2 vectors. for clinical trial applicati ... | 2011 | 22197749 |
| adeno-associated virus mediated gene therapy for retinal degenerative diseases. | retinal gene therapy holds great promise for the treatment of inherited and noninherited blinding diseases such as retinitis pigmentosa and age-related macular degeneration. the most widely used vectors for ocular gene delivery are based on adeno-associated virus (aav) because it mediates long-term transgene expression in a variety of retinal cell types and elicits minimal immune responses. inherited retinal diseases are nonlethal and have a wide level of genetic heterogeneity. many of the genes ... | 2011 | 22034031 |
| transduction of striatum and cortex tissues by adeno-associated viral vectors produced by herpes simplex virus- and baculovirus-based methods. | recombinant adeno-associated virus (aav) vectors can be engineered to carry genetic material encoding therapeutic gene products that have demonstrated significant clinical promise. these viral vectors are typically produced in mammalian cells by the transient transfection of two or three plasmids encoding the aav rep and cap genes, the adenovirus helper gene, and a gene of interest. although this method can produce high-quality aav vectors when used with multiple purification protocols, one crit ... | 2012 | 22015677 |
| worsening of cardiomyopathy using deflazacort in an animal model rescued by gene therapy. | we have previously demonstrated that gene therapy can rescue the phenotype and extend lifespan in the delta-sarcoglycan deficient cardiomyopathic hamster. in patients with similar genetic defects, steroids have been largely used to slow down disease progression. aim of our study was to evaluate the combined effects of steroid treatment and gene therapy on cardiac function. we injected the human delta-sarcoglycan cdna by adeno-associated virus (aav) 2/8 by a single intraperitoneal injection into ... | 2011 | 21931833 |
| the large rep protein of adeno-associated virus type 2 is polyubiquitinated. | five adenovirus (ad) gene products are required for efficient replication of co-infecting adeno-associated virus (aav); however, the combined net enhancement by these factors is composed of both positive and negative effects. similar to previous results with aav rep52, aav2 large rep was targeted for ubiquitination and degradation by the ad e4orf6/e1b 55 kda, cullin 5-containing, e3-ubiquitin ligase. additionally, large rep was targeted for ubiquitination via extension of ubiquitin lysine k48 an ... | 2011 | 21865444 |
| examining the cross-reactivity and neutralization mechanisms of a panel of monoclonal antibodies against adeno-associated virus serotypes 1 and 5. | neutralizing antibodies play a central role in the prevention and clearance of viral infections, but can be detrimental to the use of viral capsids for gene delivery. antibodies present a major hurdle for ongoing clinical trials using adeno-associated viruses (aavs), however relatively little is known about the antigenic epitopes of most aav serotypes or the mechanism(s) of antibody-mediated neutralization. we developed panels of aav mabs by repeatedly immunizing mice with aav serotype 1 (aav1) ... | 2011 | 22071509 |
| direct central nervous system delivery provides enhanced protection following vector mediated gene replacement in a severe model of spinal muscular atrophy. | spinal muscular atrophy (sma), an autosomal recessive neuromuscular disorder, is the leading genetic cause of infant mortality. sma is caused by the homozygous loss of survival motor neuron-1 (smn1). sma, however, is not due to complete absence of smn, rather a low level of functional full-length smn is produced by a nearly identical copy gene called smn2. despite smn's ubiquitous expression, motor neurons are preferentially affected by low smn levels. recently gene replacement strategies have s ... | 2011 | 22172949 |
| research advances in gene therapy approaches for the treatment of amyotrophic lateral sclerosis. | amyotrophic lateral sclerosis (als) is a devastating neurodegenerative disease of motor neurons that causes progressive muscle weakness, paralysis, and premature death. no effective therapy is available. research in the motor neuron field continues to grow, and recent breakthroughs have demonstrated the possibility of completely achieving rescue in animal models of spinal muscular atrophy, a genetic motor neuron disease. with adeno-associated virus (aav) vectors, gene transfer can be achieved wi ... | 2011 | 22094924 |
| successful gene therapy <i>in utero</i> for lethal murine hypophosphatasia. | hypophosphatasia (hpp), caused by mutations in the gene <i>alpl</i> encoding tissue-nonspecific alkaline phosphatase (tnalp), is an inherited systemic skeletal disease characterized by mineralization defects of bones and teeth. the clinical severity of hpp varies widely from a lethal perinatal form to mild odontohypophosphatasia showing only dental manifestations. hpp model mice (<i>akp2</i><sup>-/-</sup>) phenotypically mimic the severe infantile form of human hpp; they appear normal at birth b ... | 2011 | 22133046 |
| heparin-coated superparamagnetic nanoparticle-mediated adeno-associated virus delivery for enhancing cellular transduction. | superparamagnetic iron oxide nanoparticles (spions) have been exploited as an elegant vehicle to enhance gene delivery efficiencies in gene therapy applications. we developed a magnetically guided adeno-associated virus (aav) delivery system for enhancing gene delivery to hek293t and pc12 cell lines. wild-type aav2 and a novel aav vector, aavr3.45, which was directly evolved in a previous study to possess diverse cell tropisms, were used as gene carriers. additionally, the affinity of each viral ... | 2011 | 22016032 |
| preclinical evaluation of a clinical candidate aav8 vector for ornithine transcarbamylase (otc) deficiency reveals functional enzyme from each persisting vector genome. | ornithine transcarbamylase deficiency (otcd), the most common and severe urea cycle disorder, is an excellent model for developing liver-directed gene therapy. no curative therapy exists except for liver transplantation which is limited by available donors and carries significant risk of mortality and morbidity. adeno-associated virus 8 (aav8) has been shown to be the most efficient vector for liver-directed gene transfer and is currently being evaluated in a clinical trial for treating hemophil ... | 2011 | 22133298 |
| neutralizing antibodies against aav serotypes 1, 2, 6, and 9 in sera of commonly used animal models. | adeno-associated virus (aav)-based vectors are promising gene delivery vehicles for human gene transfer. one significant obstacle to aav-based gene therapy is the high prevalence of neutralizing antibodies in humans. until now, it was thought that, except for nonhuman primates, pre-existing neutralizing antibodies are not a problem in small or large animal models for gene therapy. here, we demonstrate that sera of several animal models of cardiovascular diseases harbor pre-existing antibodies ag ... | 2011 | 21915102 |
| transplantation of gene-modified nucleus pulposus cells reverses rabbit intervertebral disc degeneration. | intervertebral disc degeneration is the main cause of low back pain. the purpose of this study was to explore potential methods for reversing the degeneration of lumbar intervertebral discs by transplantation of gene-modified nucleus pulposus cells into rabbit degenerative lumbar intervertebral discs after transfecting rabbit nucleus pulposus cells with adeno-associated virus 2 (aav2)-mediated connective tissue growth factor (ctgf) and tissue inhibitor of metalloproteinases 1 (timp1) genes in vi ... | 2011 | 21933582 |
| innate immune responses to aav vectors. | gene replacement therapy by in vivo delivery of adeno-associated virus (aav) is attractive as a potential treatment for a variety of genetic disorders. however, while aav has been used successfully in many models, other experiments in clinical trials and in animal models have been hampered by undesired responses from the immune system. recent studies of aav immunology have focused on the elimination of transgene-expressing cells by the adaptive immune system, yet the innate immune system also ha ... | 2011 | 21954398 |
| rescue of avian adeno-associated virus from a recombinant plasmid containing deletions in the viral inverted terminal repeats. | we have previously reported the complete genome sequence of avian adeno-associated virus (aaav) strain yz-1, isolated from healthy chickens in china. in this study, we describe the successful rescue of infectious virions from a recombinant plasmid containing the genome of yz-1 with deletions in the viral inverted terminal repeats (itrs). the complete genome of yz-1 was cloned into a bacterial plasmid by a modified "a-t" cloning method. six recombinant plasmids were selected for further experimen ... | 2011 | 21947568 |
| [capsid assembly and dna encapsidation of adeno-associated virus]. | recombinant adeno-associated viral vectors (raav) have been widely used as gene therapy vectors in clinical trials. here, we reviewed the genomic structures and replication mechanisms of wt-aav. then, the assembly of capsid and the encapsidation of genomic dna, two major events during aav pakaging, was discussed in detail. although the overall pattern of virus assembly and encapsidation is known, the molecular mechanisms and the structure-function relationship involved in these processes are not ... | 2011 | 21847986 |
| improved function of the failing rat heart by regulated expression of insulin-like growth factor i via intramuscular gene transfer. | abstract current methods of gene transfer for heart disease include injection into heart muscle or intracoronary coronary delivery, approaches that typically provide limited expression and are cumbersome to apply. to circumvent these problems, we selected a transgene, insulin-like growth factor-i (igf-i), which may, in theory, have favorable effects on heart function when secreted from a remote site. we examined the feasibility and efficacy of skeletal muscle injection of adeno-associated viru ... | 2011 | 22017392 |
| sumo1-dependent modulation of serca2a in heart failure. | the calcium-transporting atpase atp2a2, also known as serca2a, is a critical atpase responsible for ca(2+) re-uptake during excitation-contraction coupling. impaired ca(2+) uptake resulting from decreased expression and reduced activity of serca2a is a hallmark of heart failure. accordingly, restoration of serca2a expression by gene transfer has proved to be effective in improving cardiac function in heart-failure patients, as well as in animal models. the small ubiquitin-related modifier (sumo) ... | 2011 | 21900893 |
| gene therapy for leber congenital amaurosis caused by rpe65 mutations: safety and efficacy in 15 children and adults followed up to 3 years. | objective: to determine the safety and efficacy of subretinal gene therapy in the rpe65 form of leber congenital amaurosis using recombinant adeno-associated virus 2 (raav2) carrying the rpe65 gene. design: open-label, dose-escalation phase i study of 15 patients (range, 11-30 years of age) evaluated after subretinal injection of the raav2- rpe65 vector into the worse-functioning eye. five cohorts represented 4 dose levels and 2 different injection strategies. main outcome measures: primary outc ... | 2011 | 21911650 |
| hepatic gene transfer in neonatal mice by aav8 vector. | for genetic diseases that manifest at a young age with irreversible consequences, early treatment is critical and essential. neonatal gene therapy has the advantages of achieving therapeutic effects before disease manifestation, low vector requirement and high vector to cell ratio, and a relatively immature immune system. therapeutic effects or long-term rescue of neonatal lethality have been demonstrated in several animal models. however, vigorous cell proliferation in the newborn stage is a bi ... | 2011 | 22098408 |
| striatal pleiotrophin overexpression provides functional and morphological neuroprotection in the 6-hydroxydopamine model. | neurotrophic factors are integrally involved in the development of the nigrostriatal system and in combination with gene therapy, possess great therapeutic potential for parkinson's disease (pd). pleiotrophin (ptn) is involved in the development, maintenance, and repair of the nigrostriatal dopamine (da) system. the present study examined the ability of striatal ptn overexpression, delivered via psueudotyped recombinant adeno-associated virus type 2/1 (raav2/1), to provide neuroprotection and fu ... | 2011 | 22008908 |
| moderate cardiac-selective overexpression of angiotensin ii type 2 receptor protects cardiac functions from ischaemic injury. | we hypothesized that moderate cardiac-selective overexpression of the angiotensin ii type 2 receptor (at2r) would protect the myocardium from ischaemic injury after a myocardial infarction (mi) induced by coronary artery ligation. for in vitro studies, adenoviral vector expressing genomic dna of at2r and enhanced green fluorescence protein (egfp) was used to overexpress at2r in rat neonatal cardiac myocytes. expression of at2r, measured by real-time pcr and immunostaining, demonstrated efficient ... | 2011 | 21967903 |
| inhibition and promotion of tumor growth with adeno-associated virus carcinoembryonic antigen vaccine and toll-like receptor agonists. | carcinoembryonic antigen (cea) is a cancer vaccines' target. several features of recombinant adeno-associated virus (raav) are attractive for vaccine applications. combining other viral vector vaccines with toll-like receptor (tlr) agonists enhances antitumor immunity. wild-type and cea transgenic (tg) mice were immunized with raav-expressing cea, the tlr9 agonist, oligodinucleotide (odn)1826 and the tlr7 agonist, imiquimod. mice were challenged with mc38 colon tumor cells and mc38 cells express ... | 2011 | 21869824 |
| adeno-associated virus-mediated rescue of the cognitive defects in a mouse model for angelman syndrome. | angelman syndrome (as), a genetic disorder occurring in approximately one in every 15,000 births, is characterized by severe mental retardation, seizures, difficulty speaking and ataxia. the gene responsible for as was discovered to be ube3a and encodes for e6-ap, an ubiquitin ligase. a unique feature of this gene is that it undergoes maternal imprinting in a neuron-specific manner. in the majority of as cases, there is a mutation or deletion in the maternally inherited ube3a gene, although othe ... | 2011 | 22174738 |
| adeno-associated virus-mediated osteoprotegerin gene transfer protects against joint destruction in a collagen-induced arthritis rat model. | objective: to evaluate the in vivo joint protection effect of recombinant adeno-associated virus-mediated gene transfer of human osteoprotegerin (raav-hopg). methods: collagen-induced arthritis (cia) rat model was established. cia rats were randomly divided into three groups: cia control group (pbs), raav-egfp (enhanced green fluorescent protein) group and raav-hopg (100μl/d) group, which received corresponding intra-articular injection treatment. the thickness of the palms and soles, arthritis ... | 2011 | 22154615 |
| elucidating the mechanisms behind sonoporation with adeno-associated virus-loaded microbubbles. | microbubbles are food and drug administration (fda) approved contrast agents for ultrasound imaging. it has been reported that applying ultrasound on drug-loaded microbubbles facilitates drug uptake by cells, due to so-named sonoporation. however, the biophysics behind sonoporation are not fully understood. it is believed that sonoporation results in a "direct" delivery of drugs in the cytoplasm of cells, though it has been suggested as well that sonoporation facilitates endocytosis which would ... | 2011 | 22014166 |
| 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 ... | 2011 | 22031238 |
| in vitro characterization of the activity of pf-05095808 a novel biological agent for hepatitis c virus therapy. | pf-05095808 is a novel biological agent for chronic hepatitis c virus (hcv) therapy. it comprises a recombinant adeno-associated virus (aav) dna vector packaged into an aav serotype 8 capsid. the vector directs expression of 3 short hairpin (sh) rnas targeted to conserved regions of the hcv genome. these shrnas are processed by the host cell into the small interfering rnas which mediate sequence specific cleavage of target regions. for small molecule inhibitors the key screens needed to assess i ... | 2011 | 22203606 |
| adeno-associated virus rep-mediated targeting of integrase-defective retroviral vector dna circles into human chromosome 19. | retroviral vectors have been employed in clinical trials for gene therapy owing to their relative large packaging capacity, alterable cell tropism, and chromosomal integration for stable transgene expression. however, uncontrollable integrations of transgenes are likely to cause safety issues, such as insertional mutagenesis. a targeted transgene integration system for retroviral vectors, therefore, is a straightforward way to address the insertional mutagenesis issue. adeno-associated virus (aa ... | 2011 | 22138242 |
| [generation of antitumor response against hepatocellular carcinoma by in vitro transduction of dendritic cells with adeno-associated virus expressing α-fetoprotein]. | to investigate the generation of antitumor response against hepatocellular carcinoma by in vitro transduction of dendritic cells (dc) with recombinant adeno-associated virus expressing α-fetoprotein (raav-afp). | 2011 | 22093940 |
| compensatory regulation of dopamine after ablation of the tyrosine hydroxylase gene in the nigrostriatal projection. | the tyrosine hydroxylase (th; ec 1.14.16.2) is a rate-limiting enzyme in the dopamine synthesis and important for the central dopaminergic system, which controls voluntary movements and reward-dependent behaviors. here, to further explore the regulatory mechanism of dopamine levels by th in adult mouse brains, we employed a genetic method to inactivate the th gene in the nigrostriatal projection using the cre-loxp system. stereotaxic injection of adeno-associated virus expressing cre recombinase ... | 2011 | 22027820 |
| self-complementary aavs induce more potent transgene product-specific immune responses compared to a single-stranded genome. | using a mouse model we show that self-complementary (sc) adeno-associated virus (aav) vectors pseudotyped with capsids of serotypes 2, 7 or 8 induce more potent transgene product-specific cd8(+) t cell and antibody responses compared to corresponding single-stranded (ss)aav vectors. these data suggest that the higher and more rapidly appearing amounts of transgene product achieved with scaav vectors may increase detrimental immune responses in gene transfer recipients. | 2011 | 22186792 |
| Rescue of synaptic plasticity and spatial learning deficits in the hippocampus of Homer1 knockout mice by recombinant Adeno-associated viral gene delivery of Homer1c. | Homer1 belongs to a family of scaffolding proteins that interact with various post-synaptic density proteins including group I metabotropic glutamate receptors (mGluR1/5). Previous research in our laboratory implicates the Homer1c isoform in spatial learning. Homer1 knockout mice (H1-KO) display cognitive impairments, but their synaptic plasticity properties have not been described. Here, we investigated the role of Homer1 in long-term potentiation (LTP) in the hippocampal CA1 region of H1-KO mi ... | 2012 | 21945599 |
| effective reduction of the interleukin-1β transcript in osteoarthritis-prone guinea pig chondrocytes via short hairpin rna mediated rna interference influences gene expression of mediators implicated in disease pathogenesis. | to ascertain a viral vector-based short hairpin rna (shrna) capable of reducing the interleukin-1β (il-1β) transcript in osteoarthritis (oa)-prone chondrocytes and detect corresponding changes in the expression patterns of several critical disease mediators. | 2011 | 21945742 |
| identification of the heparin binding site on adeno-associated virus serotype 3b (aav-3b). | adeno-associated virus is a promising vector for gene therapy. in the current study, the binding site on aav serotype 3b for the heparan sulfate proteoglycan (hspg) receptor has been characterized. x-ray diffraction identified a disaccharide binding site at the most positively charged region on the virus surface. the contributions of basic amino acids at this and other sites were characterized using site-directed mutagenesis. both heparin and cell binding are correlated to positive charge at the ... | 2011 | 22169623 |
| interleukin-10 expression induced by adeno-associated virus vector suppresses proteinuria in zucker obese rats. | varying degrees of metabolic abnormalities mediated by chronic inflammation are implicated in the chronic glomerular injuries associated with obesity. interleukin (il)-10, a pleiotropic cytokine, exerts anti-inflammatory effects in numerous biological settings. in the present study, we explored the biological benefits of adeno-associated virus (aav) vector-mediated sustained il-10 expression against the pathological renal characteristics observed in zucker fatty rats (zfrs). we injected an aav v ... | 2011 | 22113310 |
| Adeno-Associated Virus 2 Infection Requires Endocytosis through the CLIC/GEEC Pathway. | Adeno-associated viruses (AAVs) are nonpathogenic, nonenveloped, single-stranded DNA viruses in development as gene therapy vectors. AAV internalization was postulated to proceed via a dynamin-dependent endocytic mechanism. Revisiting this, we find that infectious endocytosis of the prototypical AAV, AAV2, is independent of clathrin, caveolin, and dynamin. AAV2 infection is sensitive to EIPA, a fluid-phase uptake inhibitor, but is unaffected by Rac1 mutants or other macropinocytosis inhibitors. ... | 2011 | 22177561 |
| Increased p38 mitogen-activated protein kinase signaling is involved in the oxidative stress associated with oxygen and glucose deprivation in neonatal hippocampal slice cultures. | The pathological basis of neonatal hypoxia-ischemia (HI) brain damage is characterized by neuronal cell loss. Oxidative stress is thought to be one of the main causes of HI-induced neuronal cell death. The p38 mitogen-activated protein kinase (MAPK) is activated under conditions of cell stress. However, its pathogenic role in regulating the oxidative stress associated with HI injury in the brain is not well understood. Thus, this study was conducted to examine the role of p38 MAPK signaling in n ... | 2011 | 21939459 |
| Benefits of rAAV-Mediated IGF-I Overexpression for the Long-Term Reconstruction of Human Osteoarthritic Cartilage by Modulation of the IGF-I Axis. | Administration of therapeutic genes to human osteoarthritic (OA) cartilage is a potential approach to generate effective, durable treatments against this slow, progressive disorder. Here, we tested the ability of rAAV-mediated overexpression of human insulin-like growth factor I (IGF-I) to reproduce an original surface in human OA cartilage in light of the pleiotropic activities of the factor. We examined the proliferative, survival, and anabolic effects of the rAAV-hIGF-I treatment in primary h ... | 2011 | 22160392 |
| 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 ... | 2011 | 22131069 |
| find and replace: editing human genome in pluripotent stem cells. | genetic manipulation of human pluripotent stem cells (hpscs) provides a powerful tool for modeling diseases and developing future medicine. recently a number of independent genome-editing techniques were developed, including plasmid, bacterial artificial chromosome, adeno-associated virus vector, zinc finger nuclease, transcription activator-like effecter nuclease, and helper-dependent adenoviral vector. gene editing has been successfully employed in different aspects of stem cell research such ... | 2011 | 22173708 |
| potent antitumour activity of the combination of hsv-tk and endostatin armed oncolytic adeno-associated virus for bladder cancer in vitro and in vivo. | gene therapy may offer a new tool for the treatment of bladder cancer. previously, we have shown a significant antitumour effect in bladder cancer xenografts in a nude mouse model using intratumoural herpes simple virus thymidine (hsv-tk) and endostatin gene therapy. | 2011 | 21953122 |
| adeno-associated virus vector delivery to the heart. | cardiac gene transfer may serve as a novel therapeutic approach in the treatment of heart disease. for it to reach its full potential, methods for highly efficient cardiac gene transfer must be available to investigators so that informative preclinical data can be collected and evaluated. we have recently optimized aav-mediated cardiac gene transfer protocols in both the mouse and rat. in the mouse, we have developed a procedure for intrapericardial delivery of vector in the neonate and successf ... | 2011 | 22034032 |
| transforming growth factor α transforms astrocytes to a growth-supportive phenotype after spinal cord injury. | astrocytes are both detrimental and beneficial for repair and recovery after spinal cord injury (sci). these dynamic cells are primary contributors to the growth-inhibitory glial scar, yet they are also neuroprotective and can form growth-supportive bridges on which axons traverse. we have shown that intrathecal administration of transforming growth factor α (tgfα) to the contused mouse spinal cord can enhance astrocyte infiltration and axonal growth within the injury site, but the mechanisms of ... | 2011 | 22016551 |
| directed evolution of adeno-associated virus for enhanced gene delivery and gene targeting in human pluripotent stem cells. | efficient approaches for the precise genetic engineering of human pluripotent stem cells (hpscs) can enhance both basic and applied stem cell research. adeno- associated virus (aav) vectors are of particular interest for their capacity to mediate efficient gene delivery to and gene targeting in various cells. however, natural aav serotypes offer only modest transduction of human embryonic and induced pluripotent stem cells (hescs and hipscs), which limits their utility for efficiently manipulati ... | 2011 | 22108859 |
| 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 ... | 2011 | 21918552 |
| frontotemporal lobar degeneration-related proteins induce only subtle memory-related deficits when bilaterally overexpressed in the dorsal hippocampus. | frontotemporal lobar degeneration (ftld) is a neurodegenerative disease that involves cognitive decline and dementia. to model the hippocampal neurodegeneration and memory-related behavioral impairment that occurs in ftld and other tau and tdp-43 proteinopathy diseases, we used an adeno-associated virus serotype 9 (aav9) vector to induce bilateral expression of either microtubule-associated protein tau or transactive response dna binding protein 43kda (tdp-43) in adult rat dorsal hippocampus. hu ... | 2011 | 22177996 |
| guided delivery of adeno-associated viral vectors into the primate brain. | in this review, we discuss recent developments in the delivery of adeno-associated virus-based vectors (aav), particularly with respect to the role of axonal transport in vector distribution in the brain. the use of mri-guidance and new stereotactic aiming devices have now established a strong foundation for neurological gene therapy to become an accepted procedure in interventional neurology. | 2011 | 22036906 |
| modification and labeling of aav vector particles. | adeno-associated virus (aav) has become a versatile vector platform. in recent years, powerful -techniques for the generation of tropism-modified vectors (raav-targeting vectors) and for investigation of virus-cell interaction were developed. the following chapter describes strategies for insertion of peptide ligands into the viral capsid and the subsequent characterization of capsid mutants, for producing mosaic capsids and for labeling the viral capsid chemically or genetically. | 2011 | 22034035 |
| Decreasing disease severity in symptomatic Spinal Muscular Atrophy mice following scAAV9-SMN delivery. | Spinal Muscular Atrophy, an autosomal recessive neuromuscular disorder, is the leading genetic cause of infant mortality. SMA is caused by the homozygous loss of Survival Motor Neuron-1 (SMN1). In humans, a nearly identical copy gene is present, SMN2. SMN2 is retained in all SMA patients, and encodes the same protein as SMN1. However, SMN1 and SMN2 differ by a silent C to T transition at the 5' end of exon 7, causing alternative splicing of SMN2 transcripts and low levels of full-length SMN. SMA ... | 2011 | 22029744 |
| CBP in the nucleus accumbens regulates cocaine-induced histone acetylation and is critical for cocaine-associated behaviors. | Cocaine exposure triggers molecular events that lead to long-lasting changes in brain structure and function. These changes can lead to the development of persistent and robust behavioral adaptations that characterize addiction. Recent evidence suggests the regulation of transcription via chromatin modification, such as histone acetylation, has an important role in the development of addictive behavior. Histone acetylation is regulated by histone acetyltransferases (HATs), which acetylate histon ... | 2011 | 22114264 |
| Live-cell microarray surface coatings supporting reverse transduction by adeno-associated viruses. | High-throughput live-cell microarray technologies that facilitate combinatorial screening of genes and RNA interference (RNAi) would be invaluable in the identification of key gene expression profiles involved in complex cellular behaviors. Each spot on such a microarray can comprise a unique combination of genes or RNAi packaged into gene delivery vectors. Live target cells seeded on top of the microarrays would express the combination of genetic factors, potentially leading to phenotypic chang ... | 2011 | 21988691 |
| Structure-function analysis of receptor-binding in adeno-associated virus serotype 6 (AAV-6). | Crystal structures of the AAV-6 capsid at 3Å reveal a subunit fold homologous to other parvoviruses with greatest differences in two external loops. The electrostatic potential suggests that receptor-attachment is mediated by four residues: Arg(576), Lys(493), Lys(459) and Lys(531), defining a positively charged region curving up from the valley between adjacent spikes. It overlaps only partially with the receptor-binding site of AAV-2, and the residues endowing the electrostatic character are n ... | 2011 | 21917284 |
| dsAAV8-mediated gene transfer and ß-cell expression of IL-4 and ß-cell growth factors are capable of reversing early-onset diabetes in NOD mice. | Type-I diabetes is a chronic disease mediated by autoimmune destruction of insulin-producing ß-cells. Although progress has been made towards improving diabetes-associated pathologies and the quality of life for those living with diabetes, no therapy has been effective at eliminating disease manifestations or reversing disease progression. Here, we examined whether double-stranded adeno-associated virus serotype 8 (dsAAV8)-mediated gene delivery to endogenous ß-cells of interleukin (IL)-4 in com ... | 2011 | 22089495 |
| Adeno-Associated Virus Type 2 Modulates the Host DNA Damage Response Induced by Herpes Simplex Virus 1 during Coinfection. | Adeno-associated virus type 2 (AAV2) is a human parvovirus that relies on a helper virus for efficient replication. Herpes simplex virus 1 (HSV-1) supplies helper functions and changes the environment of the cell to promote AAV2 replication. In this study, we examined the accumulation of cellular replication and repair proteins at viral replication compartments (RCs) and the influence of replicating AAV2 on HSV-1-induced DNA damage responses (DDR). We observed that the ATM kinase was activated i ... | 2012 | 22013059 |
| viral single-strand dna induces p53-dependent apoptosis in human embryonic stem cells. | human embryonic stem cells (hescs) are primed for rapid apoptosis following mild forms of genotoxic stress. a natural form of such cellular stress occurs in response to recombinant adeno-associated virus (raav) single-strand dna genomes, which exploit the host dna damage response for replication and genome persistence. herein, we discovered a unique dna damage response induced by raav transduction specific to pluripotent hescs. within hours following raav transduction, host dna damage signaling ... | 2011 | 22114676 |
| 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 ... | 2011 | 21941595 |