RNA was once considered merely the "intermediary messenger" of DNA, responsible for transporting genetic information to cellular factories. However, over the past few years, this role has been completely rewritten. RNA has evolved from an auxiliary tool in scientific research to a protagonist directly intervening in disease treatment. Its applications not only gained global attention during the COVID-19 pandemic through mRNA vaccines but are now accelerating implementation across multiple areas, including oncology, genetic diseases, immune disorders, cardiovascular conditions, and even neurodegenerative diseases. In 2024, the global RNA therapeutics market reached $8.1 billion and is projected to grow at a compound annual growth rate of 17.7% over the next decade, expected to exceed $41.3 billion by 2034. Trends do not simply drive this growth but are the result of the combined effects of technological maturity, industrial chain integration, and clinical validation.

Technical Foundation of RNA Editing

The natural occurrence of RNA editing is part of biological evolution. For example, A-to-I editing is catalyzed by the ADAR (Adenosine Deaminase Acting on RNA) family enzymes, where inosine is recognized as guanosine (G) during translation, making A-to-I editing equivalent to A-to-G coding changes. This type of editing is widely present in physiological processes, including the nervous system, immune regulation, and even viral infections. C-to-U editing is mediated by the APOBEC family and others, commonly seen in the processing of lipid metabolism-related genes. For instance, C-to-U changes in APOB mRNA produce the truncated ApoB48 protein, which participates in lipid absorption. The innovation of modern RNA editing technology lies in combining the activity of natural editing enzymes with programmable RNA targeting modules. Common strategies include:

• Guide RNA (gRNA) combined with editing enzymes: Similar to CRISPR design, using specific sequences to precisely guide editing enzymes to target RNA sites.
• Engineered RNA-binding proteins: Such as PPR (Pentatricopeptide Repeat) or RBP (RNA-binding protein) modules for highly specific RNA target recognition.
• Fusion protein strategies: Fusing ADAR catalytic domains with RNA targeting tools like Cas13, combined with RNA guide sequences to achieve customizable single-base editing.

Figure 1. Best-in-Class Mechanism of Action of KRRO-110

Technological development is accompanied by optimization of key parameters, including editing window size, off-target risks, and editing efficiency. Compared to DNA editing, the therapeutic effects of RNA editing are reversible. If unexpected effects occur, the original state can theoretically be restored by discontinuing treatment, which is particularly important for early-stage therapeutic trials.

Why RNA Editing is Clinically Attractive

The clinical value of RNA editing is primarily reflected in three aspects:

First, it can precisely repair genetic diseases caused by single-base mutations. Many rare genetic diseases require correction of only one base to restore protein function, such as Alpha-1 antitrypsin deficiency (AATD). This disease is often caused by single-point mutations in the SERPINA1 gene, where mutant proteins misfold and aggregate in liver cells, causing liver damage and emphysema. RNA editing can directly correct the base on mutant mRNA, thereby restoring protein structure and function without altering genomic DNA.

Second, it can be used for molecular regulation of acquired diseases. For example, in neurodegenerative diseases like amyotrophic lateral sclerosis (ALS), RNA editing can be used to disrupt abnormal protein aggregation interfaces, reducing toxic aggregation. For certain types of pain management, RNA editing can modulate the current characteristics of ion channel proteins to achieve symptom relief.

Third, it has characteristics of temporality and repeatable dosing. This means that in diseases requiring long-term management, RNA editing can be administered multiple times as needed without accumulating permanent changes in the genome. This provides advantages in ethics, regulation, and safety assessment.

Fourth, at the policy and regulatory level, RNA editing may have advantages over DNA editing in clinical approval pathways due to its reversibility and lower genomic risk. However, long-term safety, immune response monitoring, and multi-dose strategies still require data accumulation in clinical settings.

Overall, RNA editing is expected to become an important pillar technology in the nucleic acid drug field over the next decade, with tremendous potential especially in diseases requiring precise, controllable regulation of protein function.

Representative Research Projects and Pipeline Layout

Currently, multiple RNA editing preclinical and clinical pipelines have emerged internationally, mainly concentrated in rare genetic diseases, neurological disorders, and metabolic diseases. Examples include:

• Alpha-1 antitrypsin deficiency: Using A-to-I editing to repair SERPINA1 mRNA mutations, restoring normal secretion and function of alpha-1 antitrypsin. Such projects have shown high editing efficiency and functional recovery in animal models.
• Rare metabolic diseases: Editing mutation sites of key metabolic enzymes to inhibit harmful protein degradation or restore enzyme activity, thereby improving metabolic balance.
• ALS: Using RNA editing to disrupt abnormal folding regions of pathogenic proteins, reducing neurotoxicity. Editing targets are often known mutations or aggregation-prone structural domains.
• Chronic pain subsets: Editing ion channel-encoding RNA through RNA editing to change the electrophysiological characteristics of sodium or calcium channels, thereby reducing neuronal excitability.

Table 1. Major Companies and Clinical Pipelines in RNA Editing Therapeutics

Most of these projects use lipid nanoparticles (LNP) as delivery systems, delivering both editing enzyme mRNA and guide RNA to target cells. LNPs have already verified clinical feasibility in mRNA vaccines and are therefore directly applied to RNA editing delivery.

Figure 2. LNP-mRNA Structural Complex.

Future Trends: The RNA Era of Precision Medicine

Several clear trends are emerging for the next decade. First, personalized medicine will be implemented on a large scale. BioNTech's trials can already complete the entire process from tumor sequencing to customized vaccines within 45 days, five times faster than traditional cycles. Second, RNA therapeutics will enter more disease areas, such as using mRNA-encoded VEGF to promote myocardial repair, using RNA editing to control sodium ion channels for chronic pain treatment, and using siRNA to reduce harmful protein levels in the nervous system. Third, some companies are attempting "healthy variant introduction" - using RNA editing to replicate naturally occurring gene variants that confer resistance to certain diseases in patients, such as the CCR5Δ32 variant's resistance to HIV.

RNA therapeutics still face many challenges, including delivery precision, long-term safety, production scalability, and healthcare reimbursement. However, from a technological trend perspective, the evolution speed of this field is accelerating. When AI design, precise editing, multi-omics analysis, and clinical manufacturing form a closed loop, RNA will not only be a transporter of genetic information but a dynamically programmable life instruction system. With over 420 RNA therapeutics advancing in clinical pipelines, our understanding of disease treatment may fundamentally change - it will no longer be a passive response to symptoms but an active rewriting of life processes at the molecular level.

Creative Biogene's RNA Editing Services

Based on the CRISPR/Cas13 system, Creative Biogene's RNA editing services provide clients with a range of specific services, including targeted RNA editing, RNA base editing, and RNA modification analysis. Creative Biogene can provide one-stop CRISPR/Cas13 genome editing services according to client research needs, including crRNA design and synthesis, CRISPR/Cas13 vector construction, and Cas13 mutant fusion protein construction. The expert team can optimize design and screening for RNA sequences of interest to improve crRNA stability in target cells, achieving efficient site-specific RNA editing.

Using catalytically inactive Cas13 (dCas13) fused with ADAR2, Creative Biogene can develop RNA base editors such as REPAIR (A-to-I replacement) and RESCUE (C-to-U replacement), reducing off-target effects and achieving precise, highly specific RNA editing. Additionally, leveraging advanced CRISPR-Cas13 systems, the company can provide RNA modification analysis, including alternative splicing regulation, A-to-I and C-to-U editing, and m6A modification. Our technology platform and experienced team provide clients with full-process support, including customized experimental design, condition optimization, and result analysis, helping save time and resources while ensuring efficient project advancement.

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