e, RNA-targeted approaches include nucleic acid-based therapeutic (NBT) and small-molecule strategies. d, For mRNA delivery, functional mRNA is delivered to cells to increase protein levels using various delivery modalities such as lipid nanoparticles (LNPs). c, For gene editing, specific mutations are corrected in situ by targeted DNA-editing or RNA-editing constructs (for example, transcription activator-like effector nucleases, zinc finger nucleases, CRISPR–Cas, base editors). b, For gene therapy, viral vectors are used to deliver cDNA encoding functional proteins. a, In protein-replacement therapy, recombinant proteins are administered to replace a mutant variant or to supplement for a deficient variant in a patient. Furthermore, synthetic polypeptides are unlikely to fully recapitulate the diversity of endogenous functions of a protein that arise from alternative splicing, post-translational modifications, subcellular targeting and other regulatory mechanisms.Ĭurrently, several strategies are approved or in development to increase protein production. Notably, recombinant proteins require cold storage and frequent injections, increasing the burden on patients. However, this approach is mostly suitable for secreted proteins or enzymes and is hindered by the complex pharmacokinetics of these molecules and cost-related issues. The therapeutic use of recombinant proteins and peptides, such as insulin administration for diabetes or monoclonal antibody treatments, has been successful in the clinic for many years 5. Subsequent innovations in large-scale recombinant protein production and purification techniques opened the way for the advancement of this approach into the clinic. Historically, one of the first clinically available NBT types for protein upregulation, namely protein replacement, employed cloning of the insufficient protein followed by its expression in cultured bacterial, human, or insect cells, purification and injection into patients (Fig. Simultaneously, innovations in chemical structure and manufacturing processes of nucleic acid-based therapeutics (NBTs) have added a powerful modality to small-molecule approaches to access these networks 4. It has since become clear that these newly discovered long non-coding RNA (lncRNA) transcripts have important biological functions and are core players in the vast RNA-based regulatory networks that affect all aspects of intracellular protein synthesis 2, 3. The research revealed that, surprisingly, while approximately three-quarters of the genome sequence is transcribed, only around 1% of the human genome codes for proteins 1. The breakthrough moment in this area came in the early 2000s, after the completion of the human genome project. While efficacious in many contexts, this paradigm had not been easily applied to the multitude of diseases that are caused by insufficient expression of biologically vital proteins. In general, it has been easier to find such molecules with inhibitory or antagonistic effects 1. Traditionally, therapeutic development involved the discovery of protein-targeting small molecules. This Review highlights emerging RNA-targeted therapeutics for gene activation, focusing on opportunities and challenges for translation to the clinic. Such approaches can directly target the stability of mRNAs or modulate non-coding RNA-mediated regulation of transcription and translation. In addition to RNA-targeting small molecules, new nucleic acid-based therapeutic modalities that allow highly specific modulation of RNA-based regulatory networks are being developed. Recent discoveries of the extensive regulatory networks formed by non-coding RNAs offer alternative targets and strategies to amplify the production of a specific protein. Protein replacement and gene therapy can achieve the goal of increased protein expression but have limitations. However, in drug development, it has been historically easier to develop drugs with inhibitory or antagonistic effects. Many diseases are caused by insufficient expression of mutated genes and would benefit from increased expression of the corresponding protein.
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