The success of mRNA vaccines has sparked a surge of interest in RNA-based therapies, expanding the horizon of druggable targets. Currently, small interfering RNAs and antisense oligonucleotide drugs are making strides in clinical development. Additionally, efforts are underway to develop small molecules or antisense oligonucleotides that can modulate mRNA splicing for the treatment of various diseases.
This collection of articles focuses on the mechanisms, method developments, and applications of RNA-based therapeutics. Topics range from mRNA vaccines and splicing modulators to antisense oligonucleotides, small interfering RNAs, and RNA aptamers. Exciting advancements include the direct observation of interactions between HIV Tat protein and Tat RNA aptamer in human cells using in-cell NMR technology and the development of a universal guide RNA scaffold to enhance ADAR-mediated programmable RNA base editing.
One notable challenge in RNA therapy is delivering functional cargoes into cells effectively. Engineered extracellular vesicles show promise in this regard, enabling the delivery of CRISPR/Cas9-ribonucleoproteins both in vitro and in vivo. Another breakthrough involves a berberine-inspired lipid nanoparticle system that enhances brain targeting, potentially revolutionizing the treatment of neurological diseases by overcoming the blood-brain barrier.
Harnessing the power of splice-site creating variants (SSCVs) using transcriptome data offers a novel approach for developing therapies with antisense oligonucleotides. Screening over 300,000 publicly available transcriptomes has led to the identification of 30,130 SSCVs, opening new avenues for precision medicine. Circular RNA circRSU1 has been implicated in diabetic retinopathy, showcasing the potential of RNA therapeutics in addressing vascular dysfunction.
The development of engineered suppressor tRNAs to combat pathogenic nonsense mutations and the use of splice-modifying drugs like risdiplam and branaplam for spinal muscular atrophy highlight the diverse strategies being pursued in the RNA therapeutics space. Moreover, the ability to deliver mRNA to resting T cells for reversing HIV latency and monitoring mRNA vaccine antigen expression in vivo using PET imaging underscore the versatility and potential impact of RNA-based therapies.
Key Takeaways:
– RNA-based therapies are expanding the scope of druggable targets, with advancements in mRNA vaccines, splicing modulators, and base editing technologies.
– Engineered extracellular vesicles and lipid nanoparticle systems are revolutionizing the delivery of RNA therapeutics, especially for neurological diseases and brain targeting.
– Transcriptome data analysis is enabling the identification of splice-site creating variants for precision medicine applications.
– RNA therapeutics show promise in diverse areas such as diabetic retinopathy, muscular dystrophy, and metabolic diseases, offering new avenues for treatment.
Tags: genome editing, lipid nanoparticles, formulation
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