Review articleThe Yin and Yang of nucleic acid-based therapy in the brain

- We introduce our current understanding on the functional output of the mammalian genome, paying special attention to long non-coding RNAs and their potential applications in molecular therapy.
- We discuss the challenges for the molecular therapy in the brain and we highlight the renaissance of nucleic acid-based drugs to treat neurodegenerative diseases. We describe the potential therapeutic effects that can be obtained by inhibiting (Yin) and increasing (Yang) gene expression.
- The Yin side of nucleic acid-based therapy: we summarize the current technologies and we provide examples of their applications to treat to neurodegenerative diseases in mouse models and in clinical trials.
- The Yang side of nucleic acid-based therapy: we discuss the molecular basis of new classes of activatory RNA-based drugs, acting at the transcriptional (saRNAs and NMHVs) and translational (SINEUPs) levels. We provide examples of activatory RNA therapy in neurodegenerative disorders in mouse models and in clinical trials.
- We conclude with our vision on the future perspectives of nucleic acid-based therapy in the brain.

The post-genomic era has unveiled the existence of a large repertory of non-coding RNAs and repetitive elements that play a fundamental role in cellular homeostasis and dysfunction. These may represent unprecedented opportunities to modify gene expression at the right time in the correct space in vivo, providing an almost unlimited reservoir of new potential pharmacological agents. Hijacking their mode of actions, the druggable genome can be extended to regulatory RNAs and DNA elements in a scalable fashion.Here, we discuss the state-of-the-art of nucleic acid-based drugs to treat neurodegenerative diseases. Beneficial effects can be obtained by inhibiting (Yin) and increasing (Yang) gene expression, depending on the disease and the drug target. Together with the description of the current use of inhibitory RNAs (small inhibitory RNAs and antisense oligonucleotides) in animal models and clinical trials, we discuss the molecular basis and applications of new classes of activatory RNAs at transcriptional (RNAa) and translational (SINEUP) levels.