advancing drug discovery and development
At Chimerna, we recognized the broad impacts our Tornado circularization platform can have on drug discovery. That is why in addition to developing our own pipeline of therapeutics, we aim to increase the speed and efficiency of drug development pipelines.
High-throughput screens to discovery therapeutically-relevant microRNAs
MicroRNAs make up a special class of small non-coding RNAs in our cells. They regulate gene expression by binding to an mRNA that encodes for a protein and this results in degradation of the mRNA. Aberrant microRNA expression has been shown to play a major role in a wide range of diseases including cancer, heart disease, autoimmune diseases, neurodevelopmental diseases, and many more.
There has been a lot of advancement in the field of microRNA therapeutics from both the pharmaceutical industry and academic laboratories with new and more advanced chemistries and delivery modalities being developed all the time. However, a limitation preventing more therapies from being developed is a lack of understanding surounding which microRNAs are disease-drivers and which microRNAs have altered expression but do not impact disease progression.
At Chimerna, we are developing new high-throughput screens based on our Tornado platform to facilitate identification of disease-driving microRNAs. We are developing these screens based on two key technologies: one to degrade microRNAs and one to sequester microRNAs.
Target RNA‐directed miRNA degradation (TDMD)
Our cells evolved a way to rapidly and efficiently reduce levels of certain microRNAs by degrading them in a unique way called “Target RNA-directed miRNA degradation.” MicroRNAs bind a target RNA, but instead of degrading the target RNA a structural switch occurs. This switch leads instead to the microRNA being modified by an enzyme called TUTase and ultimately degraded. Chimerna scientists have reverse engineered this process using a naturally occurring noncoding RNA called Cyrano. Using Chimerna’s approach we can specifically deplete any microRNA in the cell. We therefore achieve exceptionally high levels of microRNA depletion in cells. Our scientists are designing screening libraries to allow researchers to discover which microRNAs may regulate specific pathways or diseases.
Tornado-based microRNA sponge libraries
One well-established way to inhibit the function of microRNAs is to create a molecular sponge. This sponge acts as a competitor for microRNAs binding to their normal mRNA targets. One problem with traditional linear RNA sponges is that they are expressed at levels insufficient to equal the number of microRNAs they are meant to target. Some microRNAs can exist at >100,000 copies per cell and so an adequate sponge must be in excess to be effective. Using our Tornado platform we can generate sufficient quantities of sponge RNAs to inhibit any microRNA regardless of its expression.
Technologies to increase production of recombinant proteins in mammalian cells
Many new therapies being developed are produced using recombinant technologies. Some of these proteins require proper post-translational modification and chaperones to be biologically active. As a result, these proteins must be produced in mammalian cells instead of bacterial cultures.
Production of proteins in mammalian cells is far more expensive than bacterial cells, thus increasing the cost of these therapies. Painstaking efforts are taken to increase the protein yield from these cultures. One limitation that mammalian cultures suffer from that bacterial cultures do not is low RNA expression. Transgene expressed from a T7 promoter can represent >50% of the total RNA in bacteria leading to excellent protein yields. However, even with the strongest promoters available, mRNA expression in mammalian cells doesn't even come to close to bacteria.
Chimerna scientist's have adapted our Tornado platform to express proteins from a circular RNA in mammalian cells. Since our circular RNAs are exceptionally stable we are able to reach mRNA levels 50-100 times greater than what was previously possible. With this technology in hand, Chimerna aims to revolutionize production of recombinant proteins by vastly increasing protein yields.
Chimerna scientists are also using circular RNAs for human therapy. We have developed an an approach for rapidly and efficiently synthesizing circular mRNAs in the laboratory. These circular RNAs can be administered to patients so that the patients can synthesize proteins that would be therapeutically beneficial. These include proteins for vaccination or proteins that are normally deficient in patients. Unlike the conventional approach of administering linear mRNAs, circular mRNAs have extended lifetimes, allowing continuous protein production for 1-3 weeks.