Authors’ comments on article in Human Gene Therapy

Co-delivery of viral immune evasion proteins results in increased expression of self-amplifying RNA

The concept of delivering genetic material to defective cells to treat diseases or to vaccinate healthy people against infections has been around for quite some time. Nevertheless, key challenges remain, such as efficient delivery of the material as well as duration of gene expression. Collaborative research led by scientists from TRON, the University Medical Centre of the Johannes Gutenberg University Mainz and BioNTech AG gives new insight on how a novel approach can overcome these gene delivery hurdles.

Overcoming the innate immune response

“In this study, we improved the expression of alphavirus derived self-amplifying RNA (saRNA), which is probably the most promising candidate amongst nucleic acid-based delivery platforms”, says Tim Beissert, first author of the work published in September in Human Gene Therapy. “saRNA vectors are of increasing interest for applications such as transient expression of recombinant proteins and vaccination.” saRNA however, also induces a strong  innate host immune response in transfected cells, which until now has been an obstacle to the full exploitation of this platform. The team therefore set out to examine how this unwanted immune response could be suppressed, ensuring efficient gene expression.

EKB does the job

“In previous studies, we showed that a cocktail of three vaccinia virus proteins E3, K3 and B18 (EKB) improved the expression of synthetic non-replicating mRNA”, Tim Beissert continues to elaborate. “We therefore set out to test this concept with saRNA and optimized this approach.”

“We co-delivered non-replicating mRNA encoding the EKB proteins with our gene of interest located on saRNA and looked for increased expression”, adds Mario Perkovic, co-author of the work. “We show that this strategy resulted in highly potent blocking of the immune response and in an increased expression of the encoded protein.”

The implications are manifold

Antigen-encoding saRNA is safe and, due to self-amplification, high levels of protein can by produced from even minute amounts of transfected templates. saRNA vectors are of increasing interest for applications such as transient expression of recombinant proteins and vaccination. “Our work addresses a high need for efficient gene delivery”, Tim Beissert highlights the importance of their work. “This application promises improved bioavailability of the encoded protein, reduce the effective dose and correspondingly the cost of goods of manufacture. Since vaccination of major parts of the population – like the annual influenza vaccination – require huge amounts of the vaccine, we will continue to improve saRNA potency and delivery to reach affordable costs.”