aav vector-mediated reversal of hypoglycemia in canine and murine glycogen storage disease type ia.glycogen storage disease type ia (gsd-ia) profoundly impairs glucose release by the liver due to glucose-6-phosphatase (g6pase) deficiency. an adeno-associated virus (aav) containing a small human g6pase transgene was pseudotyped with aav8 (aav2/8) to optimize liver tropism. survival was prolonged in 2-week-old g6pase (-/-) mice by 600-fold fewer aav2/8 vector particles (vp), in comparison to previous experiments involving this model (2 x 10(9) vp; 3 x 10(11) vp/kg). when the vector was pseudoty ...200818362924
the role of the adeno-associated virus capsid in gene transfer.adeno-associated virus (aav) is one of the most promising viral gene transfer vectors that has been shown to effect long-term gene expression and disease correction with low toxicity in animal models, and is well tolerated in human clinical trials. the surface of the aav capsid is an essential component that is involved in cell binding, internalization, and trafficking within the targeted cell. prior to developing a gene therapy strategy that utilizes aav, the serotype should be carefully consid ...200818369962
adeno-associated virus transfer of a gene encoding snap-25 resistant to botulinum toxin a attenuates neuromuscular paralysis associated with botulism.advances in viral gene therapy have opened new possibilities for treating a range of motor neuron diseases, but these have not yet been translated into clinically applicable therapies because of difficulties in delivery to susceptible/damaged neurons, ambiguities in the identity of gene(s) implicated, and a paucity of means to quantify any physiological improvement. most of these hurdles can be overcome by using the neuromuscular paralysis induced by botulinum neurotoxin type a (bont/a) as a pro ...200818385326
effect of late-stage therapy on disease progression in aav-mediated rescue of photoreceptor cells in the retinoschisin-deficient mouse.proof-of-concept for a successful adeno-associated virus serotype 5 (aav5)-mediated gene therapy in x-linked juvenile retinoschisis (xlrs) has been demonstrated in an established mouse model for this condition. the initial studies concentrated on early time-points of treatment. in this study, we aimed to explore the consequences of single subretinal injections administered at various stages of more advanced disease. by electroretinogram (erg), functional improvement in treated versus untreated e ...200818388913
adeno-associated virus vectors: versatile tools for in vivo gene transfer.over the last few years, viral vectors based on the adeno-associated virus have gained increasing popularity due to several favorable characteristics, including the high efficiency of transduction of postmitotic tissues in vivo and the long-term persistence of transgene expression in the absence of inflammation or immune response. recently, completed trials have substantially confirmed the clinical applicability of these vectors, while indicating that further developments in vector design and pr ...200818391585
hsp70 and constitutively active hsf1 mediate protection against cdcrel-1-mediated toxicity.defects in cellular quality control mechanisms are thought to contribute to the neuropathology of parkinson's disease (pd). overexpressing heat shock proteins (hsps) may constitute a powerful therapeutic strategy for pd, because they boost the ability of the cell to eliminate unwanted proteins. we investigated the neuroprotective potential of hsp70, hsp40, and h-bh, a constitutively active form of heat shock factor 1, in a rat model of pd based on adeno-associated virus (aav) vector-mediated ove ...200818398426
serotype-dependent packaging of large genes in adeno-associated viral vectors results in effective gene delivery in mice.vectors derived from adeno-associated virus (aav) are promising for human gene therapy, including treatment for retinal blindness. one major limitation of aavs as vectors is that aav cargo capacity has been considered to be restricted to 4.7 kb. here we demonstrate that vectors with an aav5 capsid (i.e., raav2/5) incorporated up to 8.9 kb of genome more efficiently than 6 other serotypes tested, independent of the efficiency of the raav2/5 production process. efficient packaging of the large mur ...200818414684
therapeutic potential of cere-110 (aav2-ngf): targeted, stable, and sustained ngf delivery and trophic activity on rodent basal forebrain cholinergic neurons.treatment of degenerating basal forebrain cholinergic neurons with nerve growth factor (ngf) in alzheimer's disease has long been contemplated, but an effective and safe delivery method has been lacking. towards achieving this goal, we are currently developing cere-110, an adeno-associated virus-based gene delivery vector that encodes for human ngf, for stereotactic surgical delivery to the human nucleus basalis of meynert. results indicate that ngf transgene delivery to the targeted brain regio ...200818439998
chromatography-based purification of adeno-associated virus.virus-mediated gene transfer shows great potential as a therapeutic strategy for the management of various inherited and acquired human diseases. among the current viral vectors, adeno-associated virus (aav) has become the vector of choice for numerous gene therapy applications. as aav-based vectors approach the clinic, the need for scalable methods of production and purification is steadily increasing. in this chapter, we present a column chromatography-based protocol for the purification of re ...200818470638
ability of adeno-associated virus serotype 8-mediated hepatic expression of acid alpha-glucosidase to correct the biochemical and motor function deficits of presymptomatic and symptomatic pompe mice.the availability of a murine model of pompe disease has enabled an evaluation of the relative merits of various therapeutic paradigms, including gene therapy. we report here that administration of a recombinant adeno-associated virus serotype 8 (aav8) vector (aav8/dc190-gaa) encoding human acid alpha-glucosidase (gaa) into presymptomatic pompe mice resulted in nearly complete correction of the lysosomal storage of glycogen in all the affected muscles. a relatively high dose of aav8/dc190-gaa was ...200818500944
enhanced transduction and improved photoreceptor survival of retinal degeneration by the combinatorial use of raav2 with a lower dose of adenovirus.recombinant adeno-associated virus (raav) is widely used in retinal gene therapy. enhanced raav transduction may be important for better therapeutic effects in some retinal gene therapies. in this study, we examined the effects of adenovirus 5 (ad5) on retina transduction mediated by raav2. our results provide the first evidence that low levels of either replication-incompetent or conditional replication-competent ad5 significantly enhance and accelerate transgene expression in human and rat ret ...200818513780
correction of multiple striated muscles in murine pompe disease through adeno-associated virus-mediated gene therapy.glycogen storage disease type ii (pompe disease; mim 232300) stems from the deficiency of acid alpha-glucosidase (gaa; acid maltase; ec, which primarily involves cardiac and skeletal muscles. an adeno-associated virus 2/8 (aav2/8) vector containing the muscle creatine kinase (mck) (ck1) reduced glycogen content by approximately 50% in the heart and quadriceps in gaa-knockout (gaa-ko) mice; furthermore, an aav2/8 vector containing the hybrid alpha-myosin heavy chain enhancer-/mck enhanc ...200818560415
silencing of t lymphocytes by antigen-driven programmed death in recombinant adeno-associated virus vector-mediated gene therapy.recombinant adeno-associated virus (raav) vectors are considered promising for human gene replacement because they facilitate stable expression of therapeutic proteins in transduced tissues. whether the success of gene therapy will be influenced by cellular immune responses targeting transgene-encoded proteins that are potentially immunogenic is unknown. here we characterized cd8(+) t-cell activity against beta-galactosidase and enhanced green fluorescent protein, model antigens containing major ...200918566327
human apolipoprotein e expression from mouse skeletal muscle by electrotransfer of nonviral dna (plasmid) and pseudotyped recombinant adeno-associated virus (aav2/7).plasma apolipoprotein e (apoe) has multiple atheroprotective actions. however, although liver-directed adenoviral gene transfer of apoe reverses hypercholesterolemia and inhibits atherogenesis in apoe-deficient (apoe(-/-)) mice, safety considerations have revived interest in nonviral dna (plasmid) and nonpathogenic adeno-associated viral (aav) vectors. here, we assess the effectiveness of these two delivery vehicles by minimally invasive intramuscular injection. first, we constructed aav2-based ...200818578629
the effect of surface demineralization of cortical bone allograft on the properties of recombinant adeno-associated virus coatings.freeze-dried recombinant adeno-associated virus (raav) coated structural allografts have emerged as an approach to engender necrotic cortical bone with host factors that will persist for weeks following surgery to facilitate revascularization, osteointegration, and remodeling. however, one major limitation is the nonporous cortical surface that prohibits uniform distribution of the raav coating prior to freeze-drying. to overcome this we have developed a demineralization method to increase surfa ...200818590929
prospects for retinal cone-targeted gene therapy.gene therapy strategies that target therapeutic genes to retinal cones are a worthy goal both because cone photoreceptor diseases are severely vision limiting and because many retinal diseases that do not affect cones directly eventually lead to cone loss, the reason for eventual blindness. human achromatopsia is a genetic disease of cones that renders them nonfunctional but otherwise intact. thus, animal models of achromatopsia were used in conjunction with adeno-associated virus (aav) vectors ...200818596991
leber congenital amaurosis: genes, proteins and disease mechanisms.leber congenital amaurosis (lca) is the most severe retinal dystrophy causing blindness or severe visual impairment before the age of 1 year. linkage analysis, homozygosity mapping and candidate gene analysis facilitated the identification of 14 genes mutated in patients with lca and juvenile retinal degeneration, which together explain approximately 70% of the cases. several of these genes have also been implicated in other non-syndromic or syndromic retinal diseases, such as retinitis pigmento ...200818632300
novel anti-vegf chimeric molecules delivered by aav vectors for inhibition of retinal neovascularization.vascular endothelial growth factor (vegf) is important in pathological neovascularization, which is a key component of diseases such as the wet form of age-related macular degeneration, proliferative diabetic retinopathy and cancer. one of the most potent naturally occurring vegf binders is vegf receptor flt-1. we have generated two novel chimeric vegf-binding molecules, sflt01 and sflt02, which consist of the second immunoglobulin (igg)-like domain of flt-1 fused either to a human igg1 fc or so ...200918633446
large-scale production of recombinant adeno-associated viral vectors.current and future demands of viral vectors for the development of successful pre-clinical and clinical studies in human gene therapy and possible commercialization of gene therapy products require well-established large-scale production processes. one of the most promising vectors for human gene therapy is recombinant adeno-associated virus vectors (raavs). some of the attractive features of raav are broad tissue tropism, low immunogenicity, ability to transduce both mitotic and post-mitotic ce ...200818679618
human gene targeting favors insertions over deletions.gene targeting is a powerful technique for manipulating the human genome, but few studies have directly compared the targeting frequencies of various types of vector constructs. here we show that similar targeting constructs are able to insert nucleotides at the homologous chromosomal target locus more efficiently than they can delete nucleotides, and combination insertion/deletion vectors appear to target at intermediate frequencies. this holds true for deletions ranging from 1 to 334 bp and in ...200818680404
enhancing transduction of the liver by adeno-associated viral vectors.a number of distinct factors acting at different stages of the adeno-associated virus vector (aav)-mediated gene transfer process were found to influence murine hepatocyte transduction. foremost among these was the viral capsid protein. self-complementary (sc) aav pseudotyped with capsid from serotype 8 or rh.10 mediated fourfold greater hepatocyte transduction for a given vector dose when compared with vector packaged with aav7 capsid. an almost linear relationship between vector dose and trans ...200918701909
skeletal muscle-specific expression of human blood coagulation factor ix rescues factor ix deficiency mouse by aav-mediated gene transfer.the efficacy of recombinant adeno-associated virus (aav) vector to deliver and express human blood clotting factor ix (hfix) gene in skeletal muscle of coagulation factor ix deficiency mouse strain (factorix-knockout) is evaluated. the muscle creatine kinase enhancer (mck) and beta-actin promoter (betaa) were used to drive the hfix minigene (hfixml), which was flanked by aav inverted terminal repeats (itrs). following intramuscular injection of high titer (2.5 x 10(11) vector genomes/ml) of raav ...199918726486
a novel and highly efficient production system for recombinant adeno-associated virus vector.recombinant adeno-associated virus (raav) has proven to be a promising gene delivery vector for human gene therapy. however, its application has been limited by difficulty in obtaining enough quantities of high-titer vector stocks. in this paper, a novel and highly efficient production system for raav is described. a recombinant herpes simplex virus type 1 (rhsv-1) designated hsv1-rc/deltaul2, which expressed adeno-associated virus type2 (aav-2) rep and cap proteins, was constructed previously. ...200218763068
epitope tagging of endogenous genes in diverse human cell lines.epitope tagging is a powerful and commonly used approach for studying the physical properties of proteins and their functions and localization in eukaryotic cells. in the case of saccharomyces cerevisiae, it has been possible to exploit the high efficiency of homologous recombination to tag proteins by modifying their endogenous genes, making it possible to tag virtually every endogenous gene and perform genome-wide proteomics experiments. however, due to the relative inefficiency of homologous ...200818784188
protective effect of recombinant adeno-associated virus 2/8-mediated gene therapy from the maternal hyperphenylalaninemia in offsprings of a mouse model of phenylketonuria.phenylketonuria (pku) is an autosomal recessively inherited metabolic disorder caused by a deficiency of phenylalanine hydroxylase (pah). the accumulation of phenylalanine leads to severe mental and psychomotor retardation, and the fetus of an uncontrolled pregnant female patient presents with maternal pku syndrome. we have reported previously on the cognitive outcome of biochemical and phenotypic reversal of pku in a mouse model, pahenu2, by the aav serotype 2-mediated gene delivery of a human ...200818955797
genetic vaccines for anthrax based on recombinant adeno-associated virus vectors.bacillus anthracis represents a formidable bioterrorism and biowarfare threat for which new vaccines are needed with improved safety and efficacy over current options. toward this end, we created recombinant adeno-associated virus type 1 (raav1) vectors containing synthetic genes derived from the protective antigen (pa) or lethal factor (lf) of anthrax lethal toxin (letx) and tested them for immunogenicity and induction of toxin-neutralizing antibodies in rabbits. codon-optimized segments encodi ...200919002162
short-term rescue of neonatal lethality in a mouse model of propionic acidemia by gene therapy.propionic acidemia (pa) is a metabolic disorder that causes mental retardation and that can be fatal if untreated. pa is inherited in an autosomal recessive fashion involving mutations in pcca or pccb encoding the alpha and beta subunits of propionyl-coa carboxylase (pcc). current treatment is based on dietary restriction of substrate amino acids, which attenuates symptoms. however, patients still experience episodes of hyperammonemia that can cause progressive neurologic damage. in this paper, ...200919025475
[adeno-associated virus mediated tumor necrosis factor related apoptosis inducing ligand gene transfected into hepatocellular carcinoma cells by ultrasound microbubble intensifier: an experimental study].to evaluate the impact of the recombined adeno-associated virus encoding soluble tumor necrosis factor related apoptosis inducing ligand gene (raav-strail) on proliferation and apoptosis of human hepatocellular carcinoma (hcc) cells, and to investigate the feasibility and efficiency of transfection of raav-strail into human hcc cells by ultrasound microbubble intensifier.200819040022
adeno-associated virus-mediated human c-reactive protein gene delivery causes endothelial dysfunction and hypertension in rats.prospective studies have shown that c-reactive protein (crp) is a predictor of hypertension. because of confounding variables, a causal linkage between crp and hypertension has not been clearly shown. we investigated whether high circulating concentrations of human crp can induce hypertension in rats.200919056836
functional cftr expression in cystic fibrosis airway epithelial cells by aav6.2-mediated segmental trans-splicing.cystic fibrosis is characterized by deficiency of the cystic fibrosis transmembrane conductance regulator (cftr), a cl‾ transporter. the packaging constraints of adeno-associated virus (aav) vectors preclude delivery of both an active promoter and cftr cdna to target cells. we hypothesized that segmental trans-splicing, where 2 aav vectors deliver the 5' and 3' halves of the cftr cdna, could mediate splicing of 2 pre-mrnas into a full length, functional cftr mrna. using a segmental trans-s ...200819072293
aav1-, aav2- and aav5-mediated human alpha-iduronidase gene transfer in the brain of nonhuman primate: vector diffusion and bio distribution.we have previously demonstrated that delivery of a recombinant adeno-associated virus (raav) encoding for the human alpha-iduronidase (hidua) in the putamen and centrum semiovale was feasible and beneficial in a dog model of hurlers syndrome. in the present study, we investigated the safety and vector diffusion profile of three raav serotypes (raav2/1, raav2/2 and raav2/5), encoding for the hidua in the central and peripheral nervous systems of nonhuman primates. six macaques received the same v ...200919125589
production of recombinant aav vectors encoding insulin-like growth factor i is enhanced by interaction among aav rep regulatory sequences.adeno-associated virus (aav) vectors are promising tools for gene therapy. currently, their potential is limited by difficulties in producing high vector yields with which to generate transgene protein product. aav vector production depends in part upon the replication (rep) proteins required for viral replication. we tested the hypothesis that mutations in the start codon and upstream regulatory elements of rep78/68 in aav helper plasmids can regulate recombinant aav (raav) vector production. w ...200919128486
controlling brain tumor growth by intraventricular administration of an aav vector encoding ifn-beta.glioblastoma multiforme (gbm) is the most aggressive type of all primary brain tumors, with an overall median survival <1 year after diagnosis. despite introduction of multimodal treatment approaches, the prognosis has not improved significantly over the past 50 years. in this study we investigated the effect of intracerebroventricular (icv) injection of an adeno-associated virus (aav) vector encoding human interferon-beta (aav-hifn-beta) on glioblastoma growth. recently, we found that peritumor ...200919197327
clinically relevant effects of convection-enhanced delivery of aav2-gdnf on the dopaminergic nigrostriatal pathway in aged rhesus monkeys.growth factor therapy for parkinson's disease offers the prospect of restoration of dopaminergic innervation and/or prevention of neurodegeneration. safety and efficacy of an adeno-associated virus (aav2) encoding human glial cell-derived neurotrophic factor (gdnf) was investigated in aged nonhuman primates. positron emission tomography with 6-[(18)f]-fluoro-l-m-tyrosine (fmt-pet) in putamen was assessed 3 months before and after aav2 infusion. in the right putamen, monkeys received either phosp ...200919203243
directed evolution of adeno-associated virus to an infectious respiratory virus.respiratory viruses evolve to maintain infectivity levels that permit spread yet prevent host and virus extinction, resulting in surprisingly low infection rates. respiratory viruses harnessed as gene therapy vectors have illustrated this limitation. we used directed evolution in an organotypic human airway model to generate a highly infectious adeno-associated virus. this virus mediated gene transfer more than 100-fold better than parental strains and corrected the cystic fibrosis epithelial cl ...200919237554
efficient and fast functional screening of microdystrophin constructs in vivo and in vitro for therapy of duchenne muscular dystrophy.duchenne muscular dystrophy (dmd) is an x-linked, lethal genetic disorder affecting the skeletal muscle compartment, and is caused by mutation(s) in the dystrophin gene. gene delivery of microdystrophin constructs using adeno-associated virus (aav) and antisense-mediated exon skipping restoring the genetic reading frame are two of the most promising therapeutic strategies for dmd. both approaches use microdystrophin proteins either directly as a desired construct for gene delivery, using the cap ...200919239382
induction of immune tolerance to fix following muscular aav gene transfer is aav-dose/fix-level intramuscular injection (im) of adeno-associated virus (aav) has been proven a safe and potentially efficient procedure for gene therapy of many genetic diseases including hemophilia b. it is, however, contentious whether high antigen level induces tolerance or immunity to coagulation factor ix (fix) following im of aav. we recently reported induction of fix-specific immune tolerance by im of aav serotype one (aav1) vector in mice. we hypothesize that the expression of high levels of fix ...200919240690
aav for pain: steps towards clinical translation.recombinant adeno-associated virus (raav) vectors consisting of self-complementary genomes and packaged in certain capsids can target primary sensory neurons efficiently and can control neuropathic pain long term by expressing opioid or non-opioid analgesic genes. this review examines the therapeutic potential of the approach in five sections: pain control in oncology (including a discussion of cancer centers as translational pain research environment); vector biology; safety considerations and ...200919262609
a preclinical animal model to assess the effect of pre-existing immunity on aav-mediated gene transfer.hepatic adeno-associated virus (aav)-serotype 2-mediated gene transfer results in sustained transgene expression in experimental animals but not in human subjects. we hypothesized that loss of transgene expression in humans might be caused by immune memory mechanisms that become reactivated upon aav vector transfer. here, we tested the effect of immunological memory to aav capsid on aav-mediated gene transfer in a mouse model. upon hepatic transfer of an aav2 vector expressing human factor ix (h ...200919367258
intra-articular gene delivery and expression of interleukin-1ra mediated by self-complementary adeno-associated virus.the adeno-associated virus (aav) has many safety features that favor its use in the treatment of arthritic conditions; however, the conventional, single-stranded vector is inefficient for gene delivery to fibroblastic cells that primarily populate articular tissues. this has been attributed to the inability of these cells to convert the vector to a double-stranded form. to overcome this, we evaluated double-stranded self-complementary (sc) aav as a vehicle for intra-articular gene delivery.200919384892
cervical cancer isolate pt3, super-permissive for adeno-associated virus replication, over-expresses dna polymerase delta, pcna, rfc and rpa.adeno-associated virus (aav) type 2 is an important virus due to its use as a safe and effective human gene therapy vector and its negative association with certain malignancies. aav, a dependo-parvovirus, autonomously replicates in stratified squamous epithelium. such tissue occurs in the nasopharynx and anogenitals, from which aav has been clinically isolated. related autonomous parvoviruses also demonstrate cell tropism and preferentially replicate in oncogenically transformed cells. combinin ...200919389243
aav gene therapy as a means to increase apolipoprotein (apo) a-i and high-density lipoprotein-cholesterol levels: correction of murine apoa-i deficiency.inherited apolipoprotein (apo) a-i deficiency is an orphan disorder characterized by high-density lipoprotein (hdl)-cholesterol deficiency and premature atherosclerosis. constitutive over-expression of apoa-i might provide a means to treat this disease. the present study provides a comprehensive evaluation of adeno-associated virus (aav)-mediated apoa-i gene delivery to express human (h)apoa-i and correct the low hdl-cholesterol phenotype associated with apoa-i deficiency.200919431216
activated forms of vegf-c and vegf-d provide improved vascular function in skeletal muscle.the therapeutic potential of vascular endothelial growth factor (vegf)-c and vegf-d in skeletal muscle has been of considerable interest as these factors have both angiogenic and lymphangiogenic activities. previous studies have mainly used adenoviral gene delivery for short-term expression of vegf-c and vegf-d in pig, rabbit, and mouse skeletal muscles. here we have used the activated mature forms of vegf-c and vegf-d expressed via recombinant adeno-associated virus (raav), which provides stabl ...200919443835
transient expression of genes delivered to newborn rat liver using recombinant adeno-associated virus 2/8 vivo adeno-associated virus (aav) delivery to adult liver results in sustained expression of the transgene. however, it has been suggested that aav delivery to the newborn liver may result in transient expression. in the present study, we analysed transgene expression after aav8 delivery of a therapeutic or a marker gene to newborn rat liver.200919455564
intravitreal delivery of aav8 retinoschisin results in cell type-specific gene expression and retinal rescue in the rs1-ko mouse.x-linked juvenile retinoschisis (xlrs) is a neurodevelopmental abnormality caused by retinoschisin gene mutations. xlrs is characterized by splitting through the retinal layers and impaired synaptic transmission of visual signals resulting in impaired acuity and a propensity to retinal detachment. several groups have treated murine retinoschisis models successfully using adeno-associated virus (aav) vectors. owing to the fragile nature of xlrs retina, translating this therapy to the clinic may r ...200919458650
adeno-associated virus infection of murine fibroblasts with help provided by mouse adenovirus.adeno-associated virus (aav-2) replicates to high titers when host cells are coinfected with a helper virus. here we analyzed the coinfection of aav-2 and mouse adenovirus (mav-1) in murine fibroblasts. we observed that aav-2/mav-1 coinfected nih 3t3 cells produced approximately 10-40-fold less aav-2 dnase resistant particles than hela cells. levels of aav-2 dna replication were approximately 30-fold less in 3t3 cells as compared to hela cells coinfected with human adenovirus (ad-5). a study of ...200919464040
[a preliminary study of murine hemangioma model by delivery of recombinant adeno-associated virus mediated human vascular endothelial growth factor-121 gene].to investigate the feasibility of establishing a murine hemangioma model with injection of recombinant adeo-associated virus mediated human vascular endothelial growth factor-121 (raav-hvegf(121)) gene.200919576022
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
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
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
[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
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-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
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
macrophage reverse cholesterol transport in mice expressing apoa-i 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
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
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
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
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
[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
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
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
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
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 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
adeno-associated virus harboring fusion gene nt4-ant-shepherdin induce cell death in human lung cancer 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
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
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
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
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
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
frequent endonuclease cleavage at off-target locations in 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
[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
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
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
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
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
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
[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
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
[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
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
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
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
activation of the erk signaling pathway is involved in cd151-induced angiogenic effects on the formation of cd151-integrin 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
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
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
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
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
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
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
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
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
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
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
[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
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
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
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
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
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