RNA-based therapies are a fast-growing class of drugs that utilize the cellular translational machinery and have the potential to change treatment paradigms for several diseases. Current therapeutic strategies include RNA aptamers that bind receptors to inhibit downstream signaling, RNA interference using either siRNA (small interfering RNA) or miRNA (microRNA) that bind to the endogenous mRNA sequences to promote degradation and mRNA-based therapies that impact translation11. Several RNA based therapies have been approved by regulatory agencies, and some of the first RNA therapies approved in 2016 targeted rare diseases including spinal muscular atrophy and Duchenne muscular dystrophy1. A Several RNA therapies are currently being tested in various phase I, II or III clinical trials. Notably, two mRNA vaccines from BioNTech/Pfizer and Moderna have received Emergency Use Authorization for COVID-19.
A new type of RNA, long noncoding RNA (lncRNA), is an area of active research to develop novel RNA therapies but the challenge is that these circular RNAs are poorly recognized by ribosomes. Recently, a new RNA type called endless RNA (eRNA) that combines a circular structure that can be easily translated2. aA new biotech company, Laronde Bio, was recently launched to develop eRNA based therapies. Endless RNAs contain an internal ribosomal entry site or IRES that allows ribosomes to bind to the circular RNA for translation and due to the circular structure, de novo protein synthesis is consistently going on in a loop. The circular structure makes the eRNA highly stable as RNases and other degradation machinery do not have a loose end to bind to start the RNA breakdown process. Since the eRNA is made with regular unmodified nucleotides it is likely not going to trigger an innate immune response so the residence time in the cell is expected to be long. This will allow a larger therapeutic efficacy window and allow repeated dosing to further increase the duration of therapeutic protein expression. The relatively simple structure of eRNA is likely going to support scalable manufacturing in a cost-effective manner that are highly desirable for large molecule therapies.
One of the key questions is efficient delivery of eRNA in vivo. Currently, RNA therapies are most effectively delivered via direct injection into the target organ. For example, Spinraza®, an antisense oligonucleotide therapy for spinal muscular atrophy is directly injected into the cerebrospinal fluid so that it reaches the motor neurons in the spinal cord. Another option is to link the RNA therapy to lipids, peptides, antibodies or sugar moieties to facilitate cell uptake3. With the advances in delivery of nucleic acid therapeutics, there is a good chance that the most efficient delivery method for eRNA will be identified. For now, Laronde Bio has raised $50M in financing from Flagship Pioneering and has set a lofty goal of producing 100 eRNA based medicines in 10 years4. Currently, the target diseases have not been announced but will fall into the broad areas of hematology, oncology, neurology, immunology and inflammation. One of the key advantages with eRNA is that each therapy does not need to be built from scratch – the eRNA backbone is modifiable and coding regions of various therapeutic genes can be inserted and swapped with ease. It remains to be seen if there is a size limitation on the expression cassette but for now, eRNA has the potential to fundamentally change RNA based therapies. If this technology shows clinical value, it has the potential to fundamentally alter the timelines and costs associated with drug development.
3Roberts, T.C., Langer, R. & Wood, M.J.A. Advances in oligonucleotide drug delivery. Nat Rev Drug Discov 19, 673–694 (2020).