SINEUP RNAs: a new platform for treating haploinsufficiency in autism

  • Awarded: 2022
  • Award Type: Targeted: Genomics of ASD: Pathways to Genetic Therapies
  • Award #: 1018191

Autism spectrum disorder (ASD) is a highly heterogeneous condition with a complex genetic basis. Most of the currently known genes associated with ASD harbor disruptive genomic changes, likely causing loss of function in proteins. For each gene, the basic unit of inheritance, two versions of the DNA sequence — the alleles — are inherited from each parent. Since most of the disruptive genetic changes in ASD damage only one allele, a potential therapeutic strategy resides in stimulating the intact allele to restore expression from the genomic location and rescue protein expression to physiological levels.

In this project, Marta Biagioli, Stefano Gustincich and Stefano Espinoza will exploit the SINEUPs — a new class of long non-coding RNAs (lncRNAs) able to increase target protein levels. Because of their modular and flexible structure, they can be engineered to specifically increase the production of virtually any gene of interest1-2. In recent investigations, the team has employed SINEUP to target CHD8, one of the highest confidence risk factors for ASD. Indeed, SINEUP-CHD8 was effective at rescuing traits associated with CHD8 suppression in human cells harboring reduced levels of the protein.

Building on these results, the collaborating groups aim to provide a deeper analysis of SINEUP efficacy to rescue dysfunctional phenotypes associated with Chd8 suppression in a complex in vivo mouse model. The team also wants to translate the knowledge gained studying SINEUP-CHD8 to create new active SINEUP molecules directed to other high-confidence ASD risk genes. Thus testing the hypothesis that SINEUP can represent a novel RNA-based therapy for neurodevelopmental syndromes with implications for and beyond CHD8.


  1. Carrieri C. et al. Nature 491, 454-457 (2012) PubMed
  2. Arnoldi M. et al. Methods Mol. Biol. 2434, 63-87 (2022) PubMed
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