In this project, we will exploit the modular architecture of SINEUPs, a new functional class of natural antisense long non-coding RNAs, to define a new platform of nucleic acid drugs as therapeutics for precision medicine of genetic diseases caused by Microdeletion Syndromes (MSs) and Copy Number Variations (CNVs). As a Proof-Of-Concept (POC), we will develop a therapeutic SINEUP for the 22q11.2 deletion syndrome (22q11.2DS), that is the most common MS disorder. SINEUPs are able to specifically increase endogenous protein levels of a target mRNA by enhancing its translation. In preliminary experiments, a multiSINEUP RNA able to increase at the same time the expression of DGCR8, TBX1 and COMT, have been validated. These genes are crucial for brain development and functions and are hemideleted in 22q11.2DS. By taking advantage of LgDel mice, a well-accepted animal model of the disease, a multiSINEUP-DGCR8/TBX1/COMT will be tested for rescuing diseased phenotypes in mice. Therapeutic interventions will be exclusively carried out on young adult mice to avoid any modeling of embryonic manipulation. These experiments will be instrumental to acquire sufficient preclinical data to test multiSINEUPDGCR8/ TBX1/COMT in a clinical trial for cognitive deficits and neuropsychiatric illnesses in young adults with 22q11.2DS.