Self-Amplifying RNA Approach for Protein Replacement Therapy

Abstract

Messenger RNA (mRNA) technology has already been successfully tested preclinically and there are ongoing clinical trials for protein replacement purposes; however, more effort has been put into the development of prevention strategies against infectious diseases. Apparently, mRNA vaccine approval against coronavirus disease 2019 (COVID-19) is a landmark for opening new opportunities for managing diverse health disorders based on this approach. Indeed, apart from infectious diseases, it has also been widely tested in numerous directions including cancer prevention and the treatment of inherited disorders. Interestingly, self-amplifying RNA (saRNA)-based technology is believed to display more developed RNA therapy compared with conventional mRNA technique in terms of its lower dosage requirements, relatively fewer side effects, and possessing long-lasting effects. Nevertheless, some challenges still exist that need to be overcome in order to achieve saRNA-based drug approval in clinics. Hence, the current review discusses the feasibility of saRNA utility for protein replacement therapy on various health disorders including rare hereditary diseases and also provides a detailed overview of saRNA advantages, its molecular structure, mechanism of action, and relevant delivery platforms.

Complete substitution with modified nucleotides suppresses the early interferon response and increases the potency of self-amplifying RNA

“…The current understanding in the field is that modified nucleotides (modNTPs) are incompatible with saRNA and that saRNA performance decreases proportional to incorporation percentage. In fact, multiple studies report the failure of modified saRNA, since the first discovery of the impact of modified nucleotides on mRNA [5,[16][17][18][19][20][29][30][31][32][33]. We hypothesized that modified nucleotides compatible with saRNA exist, considering the numerous RNA modifications observed in eukaryotic cells and their ubiquitous presence in RNA viruses [34].…”

mRNA in the Context of Protein Replacement Therapy

“…To address the problem of mRNA protein replacement therapies requiring doses almost an order of magnitude larger than the ones used for vaccinations, companies can switch over to newer approaches, which can produce mRNA yielding more protein per coding molecule. The employment of self-amplifying mRNA, CircRNA and Endless RNA could potentially allow for lower mRNA requirements per dose, increasing the industry’s production output per year to meet patient demands [ 137 , 138 ]. Another consideration could be the size of the protein that needs to be coded by mRNA.…”

Respiratory Syncytial Virus Infection: Treatments and Clinical Management

“…Antiviral therapies are quite a known field with almost similar technicalities and processes for different virus infections [ 81 ]. The drug development processes are quite similar and well acquainted.…”

“…Moreover, the technical barriers associated with these processes have been systematically reduced with the upgradation of biotechnologies and bioinformatics tools. The well-known platforms of bioinformatics and in silico modules are now increasingly used for in vitro modeling and clinical experimentation [ 81 , 82 ]. However, clinical experimentation and human-based models are still challenged owing to ethical health-related concerns.…”