In Vitro and In Vivo Evaluation of Human Adenovirus Type 49 as a Vector for Therapeutic Applications

Bates, Emily A.; Counsell, John R.; Alizert, Sophie; Baker, Alex; Suff, Natalie; Boyle, Ashley; Bradshaw, Angela C.; Waddington, Simon N.; Nicklin, Stuart A.; Parker, Alan L.

doi:10.3390/v13081483

Cited by 7 publications

(5 citation statements)

References 40 publications

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“…HAdV-C5 binds CAR via the engagement of the fibre knob protein. The fibre knob protein of HAdV-C5 was replaced with the fibre knob proteins of HAdV-D26 (known to use sialic acid), HAdV-B35 (binds CD46) and HAdV-D49 (receptor usage unknown [ 36 , 37 , 42 ]) to generate HAdV-C5-pseudotyped vectors. These vectors were then used to determine the transduction of these serotypes based on the fibre knob engagement.…”

Section: Discussionmentioning

confidence: 99%

Engineering Adenoviral Vectors with Improved GBM Selectivity

Bates

Lovatt

Plein

et al. 2023

Viruses

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Glioblastoma (GBM) is the most common and aggressive adult brain cancer with an average survival rate of around 15 months in patients receiving standard treatment. Oncolytic adenovirus expressing therapeutic transgenes represent a promising alternative treatment for GBM. Of the many human adenoviral serotypes described to date, adenovirus 5 (HAdV-C5) has been the most utilised clinically and experimentally. However, the use of Ad5 as an anti-cancer agent may be hampered by naturally high seroprevalence rates to HAdV-C5 coupled with the infection of healthy cells via native receptors. To explore whether alternative natural adenoviral tropisms are better suited to GBM therapeutics, we pseudotyped an HAdV-C5-based platform using the fibre knob protein from alternative serotypes. We demonstrate that the adenoviral entry receptor coxsackie, adenovirus receptor (CAR) and CD46 are highly expressed by both GBM and healthy brain tissue, whereas Desmoglein 2 (DSG2) is expressed at a low level in GBM. We demonstrate that adenoviral pseudotypes, engaging CAR, CD46 and DSG2, effectively transduce GBM cells. However, the presence of these receptors on non-transformed cells presents the possibility of off-target effects and therapeutic transgene expression in healthy cells. To enhance the specificity of transgene expression to GBM, we assessed the potential for tumour-specific promoters hTERT and survivin to drive reporter gene expression selectively in GBM cell lines. We demonstrate tight GBM-specific transgene expression using these constructs, indicating that the combination of pseudotyping and tumour-specific promoter approaches may enable the development of efficacious therapies better suited to GBM.

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Section: Discussionmentioning

confidence: 99%

Engineering Adenoviral Vectors with Improved GBM Selectivity

Bates

Lovatt

Plein

et al. 2023

Viruses

Self Cite

View full text Add to dashboard Cite

show abstract

“…Ad5 binds CAR through engagement of the fiber knob protein. The fiber knob protein of Ad5 was replaced with the fiber knob protein from Ad26 (known to use sialic acid), Ad35 (binds CD46) and Ad49 (receptor usage unknown [36], [37], [42]) to generate Ad5 pseudotyped vectors. These vectors were then used to determine the transduction of these serotypes based on the fiber knob engagement.…”

Section: Discussionmentioning

confidence: 99%

Engineering Adenoviral Vectors With Improved GBM Selectivity

Bates¹,

Lovatt²,

Plein³

et al. 2023

Preprint

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Glioblastoma (GBM) is the most common and aggressive adult brain cancer with an average survival rate of around 15 months in patients receiving standard treatment. Oncolytic adenovirus expressing therapeutic transgenes represent a promising alternative treatment for GBM. Of the many human adenoviral serotypes described to date, adenovirus 5 (Ad5) has been most utilized clinically and experimentally. However, the use of Ad5 as an anti-cancer agent may be hampered by naturally high seroprevalence rates to Ad5 coupled with infection of healthy cells via native receptors. To explore whether alternative natural adenoviral tropisms are better suited to GBM therapeutics, we pseudotyped an Ad5 based platform with the fiber knob protein from alternative serotypes. We demonstrate that the adenoviral entry receptors coxsackie and adenovirus receptor (CAR) and CD46 are highly expressed by both GBM and healthy brain tissue, whereas Desmoglein 2 (DSG2) is expressed at low level in GBM. We demonstrate that adenoviral pseudotypes, engaging CAR, CD46 and DSG2, effectively transduce GBM cells. However, the presence of these receptors on non-transformed cells presents the possibility of off-target effects and therapeutic transgene expression in healthy cells. To enhance specificity of transgene expression to GBM, we assessed the potential for tumour specific promoters hTERT and survivin to drive reporter gene expression selectively in GBM cell lines. We demonstrate tightly GBM specific transgene expression using these constructs, indicating that the combination of pseudotyping and tumour specific promoters approaches may enable the development of efficacious therapies better suited to GBM.

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“…Raw data were analyzed using FlowJo v.10, gating sequentially on cell population, singlets, and GFP-positive cells. Neuraminidase and FX transduction were carried out using luciferase-expressing vectors in the presence of 50 mU/mL neuraminidase enzyme 7 , 55 from Vibrio Cholerae (Roche, Darmstadt, Germany) or 10 μg/mL FX (Haematologic Technologies, Cambridge Bioscience, Cambridge, UK). Cell viability was measured using CellTiter-Glo Luminescent Cell Viability Assay (Promega, Madison, WI, USA), and luminescence was read using a multimode plate reader (FLUOstar Omega; BMG Labtech, Aylesbury, UK).…”

Section: Methodsmentioning

confidence: 99%