Description

 

Supervisors: Dr. Sheena Smith (group of Prof. A. Plückthun)

Email: s.smith@bioc.uzh.ch

Phone : +41 44 635 55 12

Start dates: Anytime between Sep and Nov 2020

 

Introduction: We have developed a novel gene therapy platform[1]-[2] in which adenoviruses encoding secreted therapeutic payloads are engineered to specifically transduce specific tissues. Upon in vivo administration of engineered viruses, a subpopulation of cells within the target tissue are transduced, transforming them into therapeutic ‘factories’ for the production of secreted therapeutics which act on neighboring cells in a paracrine fashion. This strategy allows for high and sustained local expression levels of efficacious therapeutics in the tissue where they are needed.

We have recently demonstrated that this system leads to highly favorable localization in delivery of cancer therapeutics to tumors (unpublished) that could have potential to treat a range of other diseases.  Accordingly, we would now like to expand applications of this gene therapy to combat COVID-19. In particular, we will adapt the adenoviral delivery platform for airway-localized production of SARS-CoV-2 neutralizing antibodies to prevent or reduce viral spread at the site of infection.

We are recruiting two M.S. thesis students to join our team and help with the engineering, purification, assessment and packaging of neutralizing antibodies for this novel anti-COVID-19 gene therapy.

 

Objectives:

1.     To engineer various formats (e.g. IgG and IgA) of neutralizing antibodies against SARS-CoV-2 or anti-inflammatory antibodies for delivery via gene therapy to the lung

2.     To express various antibodies in mammalian cell culture for characterization of stability, binding and neutralization in vitro

3.     To encode promising candidates in the adenoviral gene therapy vector for active immunizations in preclinical studies.

Overview of methodology: This project will involve standard molecular biology and biochemistry techniques, including cloning, mammalian cell culture, protein expression and purification, ELISA, SPR and DSF.  Additionally, some experimentation with pseudo-typed viruses (non-pathogenic) will allow to test neutralization. Each student will work on their own set of candidate payloads, but will be embedded in a highly collaborative environment, also obtaining guidance from other members of the Plückthun COVID-team.

 

[1]Dreier, B., Honegger, A., Hess, C., Nagy-Davidescu, G., Mittl, P.R.E., Grütter, M.G., et al. (2013). Development of a generic adenovirus delivery system based on structure-guided design of bispecific trimeric DARPin adapters. Proceedings of the National Academy of Sciences of the USA, 110 (10), E869–77.
[2] Schmid, M., Ernst, P., Honegger, A., Suomalainen, M., Zimmermann, M., Braun, L., et al. (2018). Adenoviral vector with shield and adapter increases tumor specificity and escapes liver and immune control. Nature Communications, 9(1), 1–16.