Exploring mRNA-based therapeutics beyond COVID-19 vaccines
mRNA-based therapeutics have emerged as a groundbreaking technology with vast potential beyond their well-known applications in COVID-19 vaccines. This innovative approach offers a multitude of advantages, including rapid, potent, and transient protein expression without the need for nuclear entry or risk of genomic integration. With the ability to target a wide range of diseases, from infectious diseases to cancer and monogenic disorders, mRNA therapeutics have garnered significant attention in the medical field.
The journey of mRNA technology began in 1990 when researchers demonstrated functional protein expression after direct injection of mRNA, paving the way for therapeutic applications. Over the past three decades, substantial progress has been made to enhance mRNA stability, reduce immunogenicity, and develop efficient delivery systems, culminating in the development of mRNA vaccines. The success of mRNA platforms during the COVID-19 pandemic showcased their cost-effectiveness, speed in addressing emerging crises, and overall safety.
Key advancements in mRNA technology include overcoming immunostimulatory properties through nucleoside modifications, especially pseudouridine (ψ) and N1-methylpseudouridine (m1ψ). These modifications reduce immunogenicity and toxicity, enhancing mRNA stability and expression. Additionally, optimisations in essential mRNA regions such as the 5ʹcap, untranslated regions, coding sequences, and polyadenylated tails have further improved translation efficiency and stability.
mRNA vaccines have shown promise in combatting infectious diseases such as HIV, tuberculosis, malaria, Zika virus, rabies, and influenza. These vaccines trigger immune responses by encoding pathogen antigens, leading to protective humoral and cytotoxic T-cell responses. Furthermore, mRNA-based therapies for cancer have introduced personalised vaccines targeting tumour-associated and tumour-specific antigens, showing potential in inducing anti-tumour immune responses.
In the realm of monogenic diseases, mRNA therapeutics offer new avenues for protein replacement therapy. Studies have shown promising results in treating conditions such as methylmalonic acidaemia, acute intermittent porphyria, Fabry disease, cystic fibrosis, and haemophilias. mRNA encoding hyperactive angiopoietin-1 derivatives is being explored for acute respiratory distress syndrome, highlighting the potential for extrahepatic mRNA delivery.
Immunotherapeutics using mRNA-encoded monoclonal antibodies and bispecific antibodies have shown efficacy against toxins and viral infections. Additionally, mRNA-based genomic editing has paved the way for targeted treatments of genetic disorders, with the potential for lifelong cures. Advances in mRNA technology have enabled precise gene editing and the development of novel therapeutic strategies for a wide range of diseases.
Challenges such as enhancing mRNA stability, delivery efficiency, and targetability remain to broaden the applicability of mRNA therapeutics beyond vaccines. However, ongoing research and development are crucial in optimising the mRNA platform to meet the clinical needs of various diseases. With the potential to revolutionise the treatment landscape, mRNA-based therapeutics represent a promising frontier in modern medicine.
Overall, the rapid evolution and versatility of mRNA technology offer a glimpse into a new era of medicine, where targeted, efficient, and safe treatments for a diverse array of diseases are within reach.
Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)02444-3/fulltext
The journey of mRNA technology began in 1990 when researchers demonstrated functional protein expression after direct injection of mRNA, paving the way for therapeutic applications. Over the past three decades, substantial progress has been made to enhance mRNA stability, reduce immunogenicity, and develop efficient delivery systems, culminating in the development of mRNA vaccines. The success of mRNA platforms during the COVID-19 pandemic showcased their cost-effectiveness, speed in addressing emerging crises, and overall safety.
Key advancements in mRNA technology include overcoming immunostimulatory properties through nucleoside modifications, especially pseudouridine (ψ) and N1-methylpseudouridine (m1ψ). These modifications reduce immunogenicity and toxicity, enhancing mRNA stability and expression. Additionally, optimisations in essential mRNA regions such as the 5ʹcap, untranslated regions, coding sequences, and polyadenylated tails have further improved translation efficiency and stability.
mRNA vaccines have shown promise in combatting infectious diseases such as HIV, tuberculosis, malaria, Zika virus, rabies, and influenza. These vaccines trigger immune responses by encoding pathogen antigens, leading to protective humoral and cytotoxic T-cell responses. Furthermore, mRNA-based therapies for cancer have introduced personalised vaccines targeting tumour-associated and tumour-specific antigens, showing potential in inducing anti-tumour immune responses.
In the realm of monogenic diseases, mRNA therapeutics offer new avenues for protein replacement therapy. Studies have shown promising results in treating conditions such as methylmalonic acidaemia, acute intermittent porphyria, Fabry disease, cystic fibrosis, and haemophilias. mRNA encoding hyperactive angiopoietin-1 derivatives is being explored for acute respiratory distress syndrome, highlighting the potential for extrahepatic mRNA delivery.
Immunotherapeutics using mRNA-encoded monoclonal antibodies and bispecific antibodies have shown efficacy against toxins and viral infections. Additionally, mRNA-based genomic editing has paved the way for targeted treatments of genetic disorders, with the potential for lifelong cures. Advances in mRNA technology have enabled precise gene editing and the development of novel therapeutic strategies for a wide range of diseases.
Challenges such as enhancing mRNA stability, delivery efficiency, and targetability remain to broaden the applicability of mRNA therapeutics beyond vaccines. However, ongoing research and development are crucial in optimising the mRNA platform to meet the clinical needs of various diseases. With the potential to revolutionise the treatment landscape, mRNA-based therapeutics represent a promising frontier in modern medicine.
Overall, the rapid evolution and versatility of mRNA technology offer a glimpse into a new era of medicine, where targeted, efficient, and safe treatments for a diverse array of diseases are within reach.
Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)02444-3/fulltext
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