siRNA Therapeutics for the Treatment of Hereditary Diseases and Other Conditions: A Review

RNA-based drugs hold significant potential, offering promising new treatments for a wide range of diseases, especially those with a genetic basis. By leveraging RNA interference (RNAi) and other RNA-mediated mechanisms, these therapies can precisely modulate gene expression and address the root causes of genetic defects. RNA-based drugs hold significant potential for treating a range of diseases. However, the transition of these therapies from laboratory research to clinical applications has encountered hurdles. This review explores the composition and outcomes of clinical trials for various modified short RNA drugs. We detail their mechanisms of action, delivery systems—with a focus on lipid nanoparticles and N-acetylgalactosamine (GalNAc) conjugates—and clinical efficacy in treating conditions such as transthyretin (TTR) amyloidosis. Our analysis reveals that while several RNAi-based drugs have achieved clinical approval, a critical unmet need remains: advanced delivery systems capable of precisely targeting diverse tissues, particularly outside the liver. We also underscore the importance of rigorous target validation utilising sophisticated bioinformatics tools and in vitro/in vivo assays to minimise off-target effects and ensure robust therapeutic efficacy. This review proposes a novel framework for optimising RNA drug development, emphasising the crucial interplay between delivery strategies, target specificity, and understanding disease-specific target biology.