Autism Spectrum Disorder (ASD) is a highly heterogeneous condition with complex genetic contributions. Most of the currently known high-confidence ASD risk genes harbor de novo disruptive mutations, likely causing haploinsufficiency. Given that these mutations usually affect only one allele, a potential therapeutic avenue resides in stimulating the expression from the non-mutant allele to restore the protein to physiological levels. In this project, we will exploit the modular architecture of SINEUPs - a new functional class of non-coding RNAs molecules able to increase target protein levels. Because of their modular structure, they can be artificially engineered to specifically increase the production of virtually any gene of interest. In our recent investigations, we targeted the chromodomain helicase DNA-binding 8 (CHD8), one of the strongest and independently validated risk factors for ASD. We employed synthetic SINEUP-CHD8 to efficiently stimulate endogenous CHD8 protein production. Indeed, SINEUP-CHD8 were effective in human cells with reduced levels of the target protein and in patients’-derived fibroblasts bearing CHD8 mutations to revert molecular phenotypes associated with CHD8-suppression. Thus, building on these promising results, here, we aim to provide a Proof-of-Concept towards the development of a novel RNA-based therapy for neurodevelopmental syndromes with implications for and beyond CHD8 and particularly relevant to ASDs caused by protein haploinsufficiency. We aim to provide a deeper analysis of SINEUP efficacy to rescue dysfunctional phenotypes associated to Chd8-suppression in a complex, in vivo mouse preclinical model. We also want to translate the knowledge gained studying SINEUP-CHD8 - horizontally - to synthesize new active SINEUPs targeting other strong ASD risk factors caused by dominant haploinsufficiencies. In conclusion, here we intend to provide further validation of the efficacy of RNA therapy, proposing SINEUP technology as a new RNA-based platform for therapy of genetic ASDs. We intend to share validated SINEUP reagents with the ASD community so that SINEUP therapeutic properties could be further analyzed to build pre-clinical data and streamline these molecules to the clinic.