RNA APTAMERS DO WHAT CRISPR, rna INTERFERENCE, AND OTHER DRUGS CANNOT
First developed over 30 years ago, RNA aptamers are small RNAs that fold into complex shapes that bind specific proteins. Aptamers are similar to antibodies except aptamers can function inside the cell and are made of nucleotides instead of amino acids.
Aptamers have a number of advantages when it comes to therapeutics:
To obtain highly specific RNA aptamers, we utilize a technique called Systematic Evolution of Ligands by Exponential enrichment (SELEX). In this process, a pool of random DNA sequences is made into RNA using our Tornado technology. We can then remove RNAs from the pool that bind to healthy proteins. Next, we capture RNAs that bind to a disease-causing protein variant. This is an iterative process performed over many cycles to identify RNAs with extremely high specificity for our target. After characterizing the sequence of the RNAs we can further refine specificity through structural analyses.
A key advantage of SELEX is the short time it takes to identify hits. Unlike antibody or drug screens that can take months, SELEX can be completed in a matter of weeks. This allows us to rapidly move from screening to biological testing and formulation.
RNA aptamers have key advantages over CRISPR and RNAi
CRISPR and RNAi are also RNA technologies that target DNA or mRNA in the cell. Aptamers are the third branch of RNA therapeutics and target proteins. Because RNA aptamers are so selective for binding proteins, they can selectively recognize only mutant proteins. CRISPR and RNAi are usually useful for removing entire genes or mRNAs. RNA aptamers can be highly precise and selectively inactivate mutant proteins and pathways without disrupting the genome.
RNA aptamers have key advantages over small molecules
Traditional small molecule drugs interact within the deep grooves and crevices of proteins. However, most proteins lack grooves or crevices and are therefore called “undruggable.”
RNA aptamers can bind entire surfaces of proteins to inhibit any type of protein. For this reason, RNA aptamers can bind undruggable proteins that lack any groove or crevice. Importantly, aptamers can be engineered with exquisite specificity so as to target only a disease-causing mutation in a protein. Most drugs cannot distinguish between the healthy and mutated variant of the protein—RNA aptamers excel at this.
RNA aptamers also bind to proteins that adopt unique or disease-causing shapes. For example, Alzheimer’s and Parkinson’s diseases result in aggregates of proteins in neurons that lead to neuronal death. Small molecules cannot easily disrupt the formation of these protein aggregates, but RNA aptamers can. This is because RNA aptamers can bind to the aggregated form of these proteins while not affecting the normal versions of these proteins in cells.
Why aren't more aptamers available to treat diseases?
The simple answer to this question is that RNA is simply too unstable in cells and does not reach levels necessary to inhibit the far more abundant proteins. In our cells, RNAs typically exists in thousands of copies while proteins can be 100,000 copies. There simply is not enough RNA to do the job.
This is where our Tornado technology changes everything. With Tornado-expressed aptamers it is now possible to make enough copies of stable RNA aptamers to inhibit pathogenic protein function.
At Chimerna, we are exploiting this advantage to target traditionally "undruggable" proteins for the first time.