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Adenoviral vector with shield and adapter increases tumor specificity and escapes liver and immune control.

ABSTRACT: Most systemic viral gene therapies have been limited by sequestration and degradation of virions, innate and adaptive immunity, and silencing of therapeutic genes within the target cells. Here we engineer a high-affinity protein coat, shielding the most commonly used vector in clinical gene therapy, human adenovirus type 5. Using electron microscopy and crystallography we demonstrate a massive coverage of the virion surface through the hexon-shielding scFv fragment, trimerized to exploit the hexon symmetry and gain avidity. The shield reduces virion clearance in the liver. When the shielded particles are equipped with adaptor proteins, the virions deliver their payload genes into human cancer cells expressing HER2 or EGFR. The combination of shield and adapter also increases viral gene delivery to xenografted tumors in vivo, reduces liver off-targeting and immune neutralization. Our study highlights the power of protein engineering for viral vectors overcoming the challenges of local and systemic viral gene therapies.

SUBMITTER: Schmid M

PROVIDER: S-EPMC5792622 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Adenoviral vector with shield and adapter increases tumor specificity and escapes liver and immune control.

Schmid Markus M Ernst Patrick P Honegger Annemarie A Suomalainen Maarit M Zimmermann Martina M Braun Lukas L Stauffer Sarah S Thom Cristian C Dreier Birgit B Eibauer Matthias M Kipar Anja A Vogel Viola V Greber Urs F UF Medalia Ohad O Plückthun Andreas A

Nature communications 20180131 1

Most systemic viral gene therapies have been limited by sequestration and degradation of virions, innate and adaptive immunity, and silencing of therapeutic genes within the target cells. Here we engineer a high-affinity protein coat, shielding the most commonly used vector in clinical gene therapy, human adenovirus type 5. Using electron microscopy and crystallography we demonstrate a massive coverage of the virion surface through the hexon-shielding scFv fragment, trimerized to exploit the hex ...[more]

PMID: 29386504

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Project description:The coronavirus SARS-CoV-2 (COVID19) pandemic has pushed health workers to find creative solutions to a global shortage of personal protection equipment (PPE). 3D-printing technology is having an essential role during the pandemic providing solutions for this problem, for instance, modifying full-face snorkel masks or creating low-cost face shields to use as PPE (Ishack and Lipner, 2020 [1]). Otolaryngologists are at increased occupational risk to COVID19 infection due to the exposure to respiratory droplets and aerosols, especially during the routine nose and mouth examinations where coughing and sneezing happen regularly (Rna et al., 2017 [2]; Tysome and Bhutta, 2020 [3]). The use of a headlight is essential during these examinations. However, to our knowledge, none of the commercially available or 3D-printable face shields are compatible with a headlight. Hence, using a face shield and a headlight at the same time can be very uncomfortable and sometimes impossible. To solve this problem, we have designed a 3D-printable adapter for medical headlights, which can hold a transparent sheet to create a face shield as an effective barrier protection that can be used comfortably with the headlight. The adapter can be printed in different materials with the most commonly used nowadays being the cost-efficient PLA (Polylactic Acid) used for this prototype. The resulting piece weighs only 7 g and has an estimated cost of $0.15 USD. The transparent sheets, typically made from polyester and used for laser printing, can be purchased in any office material store with a standard price of 0.4 USD per unit. After use, the transparent sheet can be easily removed. We trialed the adapter in 7 different headlights. All of these headlights accommodated the printed blocks extremely well. The headlights were used in many different settings, including the ENT clinic, the operating room, the emergency room, the ENT ward and the COVID19 intensive care unit (ICU) for a two weeks period. All doctors using the headlight felt they were fully protected from respiratory droplets, blood, sputum and other fluids. The face shield with the headlight has been found very useful for treating epistaxis, changing tracheostomy cannulas and during routine nasal and oral examinations. The headlight face shield adapter was designed to solve a specific problem among the ENT community; however other specialist can find it useful as well. Nonetheless, manufacturers should take care of specifics problems like this and provide commercially available products to protect the ENT workforce in this new era.

Dataset Information

Adenoviral vector with shield and adapter increases tumor specificity and escapes liver and immune control.

Publications

Adenoviral vector with shield and adapter increases tumor specificity and escapes liver and immune control.

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