RNA therapeutics have emerged as a pivotal innovation in modern medicine, offering targeted treatments for a range of genetic diseases. Unlike traditional therapies, RNA-based approaches aim to manipulate gene expression or replace faulty proteins, thus providing a powerful tool for combating complex diseases. This article will explore the types of RNA therapies, their mechanisms, and their significant impact on healthcare.

What Are RNA Therapeutics?

RNA therapeutics leverage the biological processes of RNA to treat diseases by influencing gene expression or providing a blueprint for protein production. These therapies encompass several categories, including:

• mRNA (messenger RNA): Used to create proteins that the body may be lacking due to genetic mutations.
• siRNA (small interfering RNA) and ASO (antisense oligonucleotides): These inhibit gene expression, targeting faulty or overactive genes.
• CRISPR-Cas9 Gene Editing: A tool that uses RNA to guide molecular “scissors” to correct specific genetic errors.

One of the most well-known applications of RNA therapeutics is mRNA vaccines, such as those used for COVID-19, although these are not classified as gene therapy since they do not alter a patient’s DNA.

The Evolution of RNA-Based Therapies

The foundation of RNA therapeutics dates back to the 1960s, when scientists first identified the intermediary role of RNA between DNA and protein production. This led to the development of mRNA therapies, which aim to replace missing or defective proteins by delivering the necessary RNA to cells. In the 1990s, researchers achieved a breakthrough by successfully injecting naked mRNA into muscle tissue, demonstrating its potential to create functional proteins in vivo.

Since then, RNA therapeutics have expanded into various fields, including cancer treatment and rare genetic disorders. The ability to deliver specific proteins through mRNA offers new possibilities for treating monogenic diseases like cystic fibrosis, where a single gene mutation disrupts protein function.

Key Mechanisms of RNA Therapeutics

RNA therapeutics work by either stimulating or inhibiting the production of proteins within cells. There are two primary approaches:

1. Protein Replacement Therapy via mRNA: This method involves introducing synthetic mRNA into cells to produce the protein that the body cannot make due to a genetic defect. For example, in cystic fibrosis, mRNA therapies aim to replace the faulty CFTR protein that regulates mucus production.
2. Gene Silencing via siRNA and ASO: These therapies interfere with the gene’s ability to produce harmful proteins by targeting the mRNA for destruction before it can be translated into a protein. This is particularly useful in diseases where an overactive or mutated gene produces too much of a harmful protein.

RNA-based therapies can be designed to target nearly any gene or protein, making them a versatile tool for treating a variety of conditions.

The Role of RNA in Gene Editing

RNA also plays a critical role in gene editing technologies, particularly the CRISPR-Cas9 system. This revolutionary tool allows scientists to make precise edits to the DNA of living organisms. Guided by RNA, the Cas9 protein cuts the DNA at a specific location, allowing for the removal or correction of faulty genes.

In clinical applications, CRISPR-Cas9 is being explored to treat conditions like sickle cell disease and HIV by editing the genes responsible for these diseases. The potential for CRISPR-Cas9 to cure genetic disorders lies in its ability to directly modify the underlying genetic code, offering long-lasting or even permanent solutions.

Clinical Applications of RNA Therapeutics

RNA therapeutics have broad applications across several fields of medicine:

• Genetic Diseases: RNA therapies can treat diseases caused by a single gene mutation, such as cystic fibrosis or Duchenne muscular dystrophy. In these cases, mRNA is used to replace missing proteins or correct faulty gene expression.
• Cancer: RNA-based treatments like siRNA and CRISPR-Cas9 are being developed to silence genes involved in tumour growth or to reprogram immune cells to better target cancer cells. CAR T-cell therapy, for instance, involves re-engineering a patient’s immune cells to fight cancer more effectively.
• Infectious Diseases: The success of mRNA vaccines against COVID-19 has sparked further research into using RNA to combat other infectious diseases. By providing cells with the instructions to make viral proteins, RNA vaccines can train the immune system to recognise and destroy the virus.

Challenges in RNA Therapeutics

Despite their potential, RNA therapies face several challenges. The main issues include:

• Stability: RNA is inherently unstable and can degrade quickly in the body, necessitating advanced delivery systems to ensure it reaches the target cells.
• Immunogenicity: Some RNA molecules can provoke immune responses, which might reduce their effectiveness or cause side effects. Researchers are working on improving RNA formulations to minimise these risks.
• Delivery: Efficiently delivering RNA therapies to the correct cells remains a significant hurdle. Lipid nanoparticles and viral vectors are two common delivery methods, but these require further refinement to ensure they are safe and effective across different patient populations.

The Future of RNA Therapeutics

The field of RNA therapeutics is rapidly evolving, with promising developments in gene editing and cancer treatment. The next generation of RNA therapies is expected to improve delivery mechanisms, making treatments more effective and accessible. One of the most exciting advancements is the potential for CRISPR-Cas9 to be used for in vivo gene editing, where genes are edited directly within the patient’s body.

Additionally, researchers are exploring the use of allogeneic CAR T-cells, which could provide off-the-shelf cancer treatments that are more cost-effective and scalable than current autologous therapies.

Conclusion

RNA therapeutics represent a major leap forward in personalised medicine, offering new hope for patients with previously untreatable conditions. As research continues, we can expect RNA-based therapies to become a cornerstone of modern medicine, transforming the treatment of genetic diseases, cancers, and infectious diseases alike. The ongoing advancements in RNA delivery systems, combined with the precision of gene editing technologies like CRISPR-Cas9, suggest a future where many genetic disorders could be cured rather than managed.

Written by Educo Life Sciences Expert, Melody Janssen

Dr. Melody Janssen is an expert in bioanalysis and immunogenicity testing of biopharmaceuticals with in-depth experience as a project manager, trainer and senior expert in CROs and pharma/biotech companies. She worked predominantly on developing and validating ligand-binding and cell-based assays for PK/Tox and immunogenicity studies for biologics, biosimilars and vaccines and her work supported numerous regulatory filings. Dr. Janssen is experienced in the regulatory framework related to bioanalytical method establishment and validation including FDA, EMA, ICH guidelines and USP and Ph.Eur. monographs.

This article was written from an interview (which you can read above) and from materials taken from the course, An Introduction to Cell and Gene Therapies: A Beginner’s Guide.