162 research outputs found
sj-pdf-1-bna-10.1177_23982128241238934 – Supplemental material for Unscheduled changes in pre-clinical stroke model housing contributes to variance in physiological and behavioural data outcomes: A post hoc analysis
No full textSupplemental material, sj-pdf-1-bna-10.1177_23982128241238934 for Unscheduled changes in pre-clinical stroke model housing contributes to variance in physiological and behavioural data outcomes: A post hoc analysis by Aisling McFall, Delyth Graham, Stuart A. Nicklin and Lorraine M. Work in Brain and Neuroscience Advances</p
sj-jpg-2-bna-10.1177_23982128241238934 – Supplemental material for Unscheduled changes in pre-clinical stroke model housing contributes to variance in physiological and behavioural data outcomes: A post hoc analysis
No full textSupplemental material, sj-jpg-2-bna-10.1177_23982128241238934 for Unscheduled changes in pre-clinical stroke model housing contributes to variance in physiological and behavioural data outcomes: A post hoc analysis by Aisling McFall, Delyth Graham, Stuart A. Nicklin and Lorraine M. Work in Brain and Neuroscience Advances</p
sj-docx-1-ltr-10.1177_13621688231176067 – Supplemental material for ‘The wisdom of crowds’: When teacher judgments outperform word-frequency as a predictor of students’ vocabulary knowledge
No full textSupplemental material, sj-docx-1-ltr-10.1177_13621688231176067 for ‘The wisdom of crowds’: When teacher judgments outperform word-frequency as a predictor of students’ vocabulary knowledge by Pablo Robles-García, Jeffrey Stewart, Christopher Nicklin, Joseph P. Vitta, Stuart McLean and Brandon Kramer in Language Teaching Research</p
Adenoviral delivery of angiotensin-(1-7) or angiotensin-(1-9) inhibits cardiomyocyte hypertrophy via the mas or angiotensin Type 2 receptor
Get PDFThe counter-regulatory axis of the renin angiotensin system peptide angiotensin-(1-7) [Ang-(1-7)] has been identified as a potential therapeutic target in cardiac remodelling, acting via the mas receptor. Furthermore, we recently reported that an alternative peptide, Ang-(1-9) also counteracts cardiac remodelling via the angiotensin type 2 receptor (AT(2)R). Here, we have engineered adenoviral vectors expressing fusion proteins which release Ang-(1-7) [RAdAng-(1-7)] or Ang-(1-9) [RAdAng-(1-9)] and compared their effects on cardiomyocyte hypertrophy in rat H9c2 cardiomyocytes or primary adult rabbit cardiomyocytes, stimulated with angiotensin II, isoproterenol or arg-vasopressin. RAdAng-(1-7) and RAdAng-(1-9) efficiently transduced cardiomyocytes, expressed fusion proteins and secreted peptides, as demonstrated by western immunoblotting and conditioned media assays. Furthermore, secreted Ang-(1-7) and Ang-(1-9) inhibited cardiomyocyte hypertrophy (Control = 168.7±8.4 µm; AngII = 232.1±10.7 µm; AngII+RAdAng-(1-7) = 186±9.1 µm, RAdAng-(1-9) = 180.5±9 µm; P<0.05) and these effects were selectively reversed by inhibitors of their cognate receptors, the mas antagonist A779 for RAdAng-(1-7) and the AT(2)R antagonist PD123,319 for RAdAng-(1-9). Thus gene transfer of Ang-(1-7) and Ang-(1-9) produces receptor-specific effects equivalent to those observed with addition of exogenous peptides. These data highlight that Ang-(1-7) and Ang-(1-9) can be expressed via gene transfer and inhibit cardiomyocyte hypertrophy via their respective receptors. This supports applications for this approach for sustained peptide delivery to study molecular effects and potential gene therapeutic actions
What matters in Cardiovascular Research? Scientific discovery driving clinical delivery
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A novel mechanism of action for angiotensin-(1-7) via the angiotensin type 1 receptor
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Tropism-modification strategies for targeted gene delivery using adenoviral vectors
Get PDFAchieving high efficiency, targeted gene delivery with adenoviral vectors is a long-standing goal in the field of clinical gene therapy. To achieve this, platform vectors must combine efficient retargeting strategies with detargeting modifications to ablate native receptor binding (i.e. CAR/integrins/heparan sulfate proteoglycans) and “bridging” interactions. “Bridging” interactions refer to coagulation factor binding, namely coagulation factor X (FX), which bridges hepatocyte transduction in vivo through engagement with surface expressed heparan sulfate proteoglycans (HSPGs). These interactions can contribute to the off-target sequestration of Ad5 in the liver and its characteristic dose-limiting hepatotoxicity, thereby significantly limiting the in vivo targeting efficiency and clinical potential of Ad5-based therapeutics. To date, various approaches to retargeting adenoviruses (Ad) have been described. These include genetic modification strategies to incorporate peptide ligands (within fiber knob domain, fiber shaft, penton base, pIX or hexon), pseudotyping of capsid proteins to include whole fiber substitutions or fiber knob chimeras, pseudotyping with non-human Ad species or with capsid proteins derived from other viral families, hexon hypervariable region (HVR) substitutions and adapter-based conjugation/crosslinking of scFv, growth factors or monoclonal antibodies directed against surface-expressed target antigens. In order to maximize retargeting, strategies which permit detargeting from undesirable interactions between the Ad capsid and components of the circulatory system (e.g. coagulation factors, erythrocytes, pre-existing neutralizing antibodies), can be employed simultaneously. Detargeting can be achieved by genetic ablation of native receptor-binding determinants, ablation of “bridging interactions” such as those which occur between the hexon of Ad5 and coagulation factor X (FX), or alternatively, through the use of polymer-coated “stealth” vectors which avoid these interactions. Simultaneous retargeting and detargeting can be achieved by combining multiple genetic and/or chemical modifications
Gene delivery to cardiovascular tissue
No full textA major hurdle in the development of cardiovascular gene therapy is the limited availability of vectors that are tissue- or cell-selective and the need for sufficient longevity of transgene expression in vivo. Nonviral vectors tend to be limited by their low transfection efficiencies and transient gene expression. Viral vectors are more promising, as they can mediate higher levels of transgene expression and are being developed to be more selective for their target organ or cell type. Strategies to improve targeting and reduce immunogenicity have been applied to adenovirus and adeno-associated viral vectors for applications in cardiovascular gene therapy. The discovery of alternate serotypes of adeno-associated virus vectors that have a natural tropism for the myocardium has greatly aided the development of optimal cardiovascular gene delivery
Development of targeted viral vectors for cardiovascular gene therapy
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Adenoviral vectors
No full textAdenoviruses are one of the most widely investigated vectors for gene therapy. Their attributes include ease of genetic manipulation to produce replication-deficient vectors, ability to readily generate high titer stocks, efficiency of gene delivery into many cell types and ability to encode large genetic inserts. Adenoviruses have been utilized for a variety of therapeutic applications particularly for high level transient overexpression in cancer gene therapy, vaccine delivery and certain cardiovascular diseases. With the first licensing of clinical adenoviral gene therapy for cancer treatment the use of adenoviruses is likely to expand in the future. This chapter focuses on the history of adenovirus development, interactions with the host both for gene delivery and immunogenicity as well as potential therapeutic applications
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