Self-amplifying RNA (saRNA) is a type of mRNA molecule engineered to replicate itself within host cells, enhancing protein expression and boosting the immune response, making it a promising tool for vaccines and other therapeutic applications. As a "next-generation" mRNA, saRNA is designed to achieve greater protein expression with a reduced dose compared to conventional mRNA.[1][2][3] Unlike conventional mRNA, which has a short short half-life and limited ability to express proteins for an extended time, saRNA can sustain protein expression for longer periods. saRNA are based on positive single stranded RNA viruses most commonly alphaviruses such as Venezuelan equine encephalitis virus.
Conventional messenger RNA (mRNA) vaccines only produce a finite amount of protein due to the short mRNA half-life. saRNA extends the kinetics of expression by a second ORF encoding the protein machinery necessary for its own replication. This self-replication dramatically increases both the amount of RNA and the time of expression. Consequently, the amount of protein produced from the initial dose is reduced as compared to conventional mRNA.[1][2]
Structure and mechanism of action
editThe structure of saRNA includes two key components:[4]
Replicon region
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saRNA encode for the machinery to replicate and amplify the mRNA in its open reading frame (shown in orange), which is the viral RNA dependent RNA polymerase (RdRp). This is a single polypeptide of viral non-structural proteins that is processed into the four protein components of the RNA dependent RNA polymerase (nsp1, nsp2, nsp3 and nsp4).
Gene of interest
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This sequence encodes the protein of interest, used as an antigen in the case of vaccines or for protein replacement therapies. The gene of interest replaces the viral structural proteins. The RNA polymerase encoded by the non-structural proteins, transcribes the gene of interest from a specific promoter (the subgenomic promoter). This subgenomic mRNA encoding the gene of interest is produced at high levels and is capped by a protein component of the non-structural proteins.
Advantages
editThe self-replicating and amplifying nature of saRNA results in high levels of protein expression even at small doses, significantly enhancing the immune response. Additionally, saRNA vaccines can be manufactured more rapidly and at a lower cost compared to traditional vaccines. saRNA also offers stability by inducing a prolonged immune response, potentially providing longer-lasting protection. Furthermore, this versatile technology can be adapted for a wide range of applications, including infectious diseases, cancer immunotherapy, and genetic disorders.
Applications and research
editThe COVID-19 pandemic has accelerated research into RNA-based technologies, including saRNA. For instance, saRNA vaccines targeting SARS-CoV-2 have shown promising results in preclinical studies, indicating strong and durable immune responses with minimal adverse effects.[5][6][7] Recently an saRNA booster vaccine developed by Arcturus (ARCT-154) has received full approval for use in adults by Japan's Ministry of Health, Labour and Welfare.[8]
saRNA is also being explored for gene therapy. Its ability to produce high levels of therapeutic proteins makes it a promising candidate for treating genetic disorders where protein replacement is needed.[9]
Challenges and future directions
editWhile saRNA technology holds great promise, it also faces several challenges. Efficient and safe delivery of saRNA into target cells remains a critical hurdle, with lipid nanoparticles (LNPs) and other delivery systems currently being optimized to address this issue. Ensuring the long-term safety of saRNA is also important, and ongoing research is focused on minimizing potential side effects and immune reactions.
References
edit- ^ a b Blakney AK, Ip S, Geall AJ (January 2021). "An Update on Self-Amplifying mRNA Vaccine Development". Vaccines. 9 (2): 97. doi:10.3390/vaccines9020097. PMC 7911542. PMID 33525396.
- ^ a b Bloom K, van den Berg F, Arbuthnot P (April 2021). "Self-amplifying RNA vaccines for infectious diseases". Gene Therapy. 28 (3–4): 117–129. doi:10.1038/s41434-020-00204-y. PMC 7580817. PMID 33093657.
- ^ Silva-Pilipich N, Beloki U, Salaberry L, Smerdou C (March 2024). "Self-Amplifying RNA: A Second Revolution of mRNA Vaccines against COVID-19". Vaccines. 12 (3): 318. doi:10.3390/vaccines12030318. PMC 10974399. PMID 38543952.
- ^ Pourseif MM, Masoudi-Sobhanzadeh Y, Azari E, Parvizpour S, Barar J, Ansari R, et al. (November 2022). "Self-amplifying mRNA vaccines: Mode of action, design, development and optimization". Drug Discovery Today. 27 (11): 103341. doi:10.1016/j.drudis.2022.103341. PMID 35988718.
- ^ Saraf A, Gurjar R, Kaviraj S, Kulkarni A, Kumar D, Kulkarni R, et al. (May 2024). "An Omicron-specific, self-amplifying mRNA booster vaccine for COVID-19: a phase 2/3 randomized trial". Nature Medicine. 30 (5): 1363–1372. doi:10.1038/s41591-024-02955-2. PMC 11108772. PMID 38637636.
- ^ Oda Y, Kumagai Y, Kanai M, Iwama Y, Okura I, Minamida T, et al. (April 2024). "Persistence of immune responses of a self-amplifying RNA COVID-19 vaccine (ARCT-154) versus BNT162b2". The Lancet. Infectious Diseases. 24 (4): 341–343. doi:10.1016/S1473-3099(24)00060-4. PMID 38310906.
- ^ Oda Y, Kumagai Y, Kanai M, Iwama Y, Okura I, Minamida T, et al. (April 2024). "Immunogenicity and safety of a booster dose of a self-amplifying RNA COVID-19 vaccine (ARCT-154) versus BNT162b2 mRNA COVID-19 vaccine: a double-blind, multicentre, randomised, controlled, phase 3, non-inferiority trial". The Lancet. Infectious Diseases. 24 (4): 351–360. doi:10.1016/S1473-3099(23)00650-3. PMID 38141632.
- ^ "First self-amplifying mRNA vaccine approved". Nature Biotechnology. 42 (1): 4. January 2024. doi:10.1038/s41587-023-02101-2. PMID 38233659.
- ^ Papukashvili D, Rcheulishvili N, Liu C, Ji Y, He Y, Wang PG (October 2022). "Self-Amplifying RNA Approach for Protein Replacement Therapy". International Journal of Molecular Sciences. 23 (21): 12884. doi:10.3390/ijms232112884. PMC 9655356. PMID 36361673.