Lecture Series: Designing ionizable lipids and lipid nanoparticles for mRNA vaccines
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TITLE: Designing ionizable lipids and lipid nanoparticles for mRNA vaccines
Michael D. Buschmann1, Manuel Carrasco1, Suman Alishetty1, Hooda Said1, Lacey Wright1, Mikell Paige2, Pat Gillevet3, Aarthi Narayanan4, Mohamad-Gabriel Alameh5, Ousamah Soliman5, Drew Weissman5, Thomas E. Cleveland IV6, Alexander Grishaev6
1Department of Bioengineering, George Mason University
4400 University Drive, MS 1J7, Fairfax, VA 22030
2Department of Chemistry & Biochemistry, George Mason University
4400 University Drive, Fairfax, VA 22030
3Department of Systems Biology, George Mason University
4400 University Drive, Fairfax, VA 22030
4Department of Biology, George Mason University
4400 University Drive, Fairfax, VA 22030
5Perelman School of Medicine, University of Pennsylvania
410B Hill Pavilion, 380 S. University Ave, Philadelphia, PA 19104
6Institute for Bioscience and Biotechnology Research
National Institute of Standards and Technology
9600 Gudelsky Dr., Rockville, MD 20850
ABSTRACT: Covid-19 mRNA vaccines are mainly composed of lipids (95% w/w) to effectively deliver the mRNA payload (5% w/w) that is translated intracellularly at the injection site and in the draining lymph nodes to stimulate the immune system to mount a humeral response to the protein immunogen. The key component of the lipid nanoparticle (LNP) delivery system is an ionizable lipid that binds the mRNA during assembly of the mRNA LNP and effectively releases it intracellularly when triggered by endosomal protonation. The success of mRNA vaccines are due in large part to their efficient delivery by the ionizable lipid and the immune adjuvant properties of the ionizable lipid. We have developed a novel rational approach to design more effective ionizable lipids starting with a theoretical assessment of their ionization properties that effect endosomal release. The resulting ionization properties are then assessed molecularly as well as in the colloidal state of the LNP and related to delivery efficiency in vitro and in vivo. In parallel we assess local inflammatory reactions and non-frozen storage properties to ensure translatability to human clinical trials. This systematic approach has resulted in a number of novel LNPs that exhibit greater potency than the current reference LNPs including their ability to protect against a lethal viral challenge in an animal model.
BIO: Michael Buschmann is the Chair of Bioengineering at George Mason University since 2017. He was previously Professor of Biomedical Engineering and Chemical Engineering at Polytechnique de Montréal from 1994 to 2017 where his biomaterials research resulted in successful clinical translation of a cartilage repair product and new nanovectors for the delivery of nucleic acids. He is currently focusing on ionizable lipids to deliver messenger RNA for vaccines.
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