Nature Outlook |

RNA therapies

Two key drug approvals have re-energised the field after a period of uncertainty.

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Articles

With more than a dozen RNA therapies being tested in clinical trials, patients with many previously untreatable conditions have cause for optimism.

Outlook | | Nature

Treatments that target RNA or deliver it to cells fall into three broad categories, with hybrid approaches also emerging.

Outlook | | Nature

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Ataxin-2 polyglutamine expansions increase the risk for amyotrophic lateral sclerosis (ALS) and cause spinocerebellar ataxia type 2 (SCA2), two neurodegenerative diseases without a cure. A pair of papers this week report therapeutic approaches towards reducing ataxin-2. Nearly all ALS patients have toxic aggregates of the protein TDP-43 in the brain and spinal cord. Lowering ataxin-2 has been shown to suppress TDP-43 toxicity in yeast and flies, and Lindsay Becker et al. now show that lowering ataxin-2 in mice, genetically or with antisense oligonucleotides, reduces TDP-43 aggregation and toxicity, improves motor function and increases lifespan. Elsewhere in this issue, Daniel Scoles et al. test antisense oligonucleotides (ASOs) against ataxin-2 in mice models of SCA2 that recreate progressive adult-onset dysfunction and degeneration of the neuronal network. The most promising therapeutic lead is ASO7, which downregulates ATXN2 mRNA and protein and delays the onset of SCA2 phenotypes. Moreover, treatment of symptomatic mice normalizes firing of cerebellar Purkinje cells and improves motor functioning. Both papers suggest that antisense oligonucleotide-based therapeutic approaches could be used to tackle neurodegeneration.

Letter | | Nature

Ataxin-2 polyglutamine expansions increase the risk for amyotrophic lateral sclerosis (ALS) and cause spinocerebellar ataxia type 2 (SCA2), two neurodegenerative diseases without a cure. A pair of papers this week report therapeutic approaches towards reducing ataxin 2. Daniel Scoles et al. test antisense oligonucleotides (ASOs) against ataxin-2 in mice models of SCA2 that recreate progressive adult-onset dysfunction and degeneration of the neuronal network. The most promising therapeutic lead is ASO7, which downregulates ATXN2 mRNA and protein and delays the onset of SCA2 phenotypes. Moreover, treatment of symptomatic mice normalizes firing of cerebellar Purkinje cells and improves motor functioning. Nearly all ALS patients have toxic aggregates of the protein TDP-43 in the brain and spinal cord. Lowering ataxin-2 has been shown to suppress TDP-43 toxicity in yeast and flies, and, elsewhere in this issue, Lindsay Becker et al. show that lowering ataxin-2 in mice, genetically or with antisense oligonucleotides, reduces TDP-43 aggregation and toxicity, improves motor function and increases lifespan. Both papers suggest that antisense oligonucleotide-based therapeutic approaches could be used to tackle neurodegeneration.

Letter | | Nature

The therapeutic potential ofin vitro-transcribed mRNA (IVT mRNA) extends from prophylactic and therapeutic vaccines to applications such as protein replacement and genome engineering. In this Review, the authors describe the recent developments in the IVT mRNA field, discuss the class-specific challenges with regards to translating IVT mRNA into a biopharmaceutical, and provide an overview of IVT mRNA drugs in development for different indications.

Review Article | | Nature Reviews Drug Discovery

In this Review, Pastoret al. provide an overview of RNA-based agents used in cancer immunotherapy — ranging from RNA vaccines encoding cancer neoantigens to interference RNAs and protein-binding RNA aptamers — providing insights into this emerging field.

Review Article | | Nature Reviews Drug Discovery