Defective gene expression is recognized as the key risk factor in NDDs, as well as in other diseases (neurodegeneration, cancer and cardiovascular). Pathologies linked to defective gene expression are hardly tractable and no scalable therapeutic approaches are presently available. Two primary issues must be addressed in order to develop robust strategies for therapeutic interventions in NDDs: identify genes involved in the pathological process and synthesize molecules capable of modulating gene expression; rationally design carriers for the specific delivery of these therapeutic molecules to cells in the CNS.
At least three haploinsufficient genes, which are heavily implicated in neuronal physiology and NDD development, will be considered: Euchromatine histone methyl transferase 1 (Ehmt1), which is associated with developmental delay and intellectual disability, severely limited or absent speech, weak muscle tone; Forkhead box G1 (Foxg1), which is associated with impaired development, structural brain abnormalities, motor and behaviourial abnormalities; Frataxin (FXN), which is associated with impaired muscle coordination, loss of strength and sensation in the arms and legs; muscle stiffness; and impaired speech, hearing, and vision.
The physiological expression of these genes will be restored by means of small molecules and ad hoc designed nucleic acids. Three classes of RNA devices will be considered for promoting gene expression: small activating RNAs (saRNAs) and RNA-programmable NMHV transactivators, both stimulating transcription, and non-coding RNAs SINEUPs, enhancing mRNA-specific translation. To date, tenths of genes have been successfully stimulated by saRNAs, and several ones by NMHV transactivators and SINEUPs. All these effectors are relatively small, expression gain they elicit is often moderate (< 3x), i.e. adequate to precise correction of haploinsufficiencies, and their activity limited to active genes. As such, these devices can outperform popular CRISPR transactivators, as easier to deliver, more confortable to tune and less biohazardous to use. Alone or combined, they are powerful and flexible tools, suitable to fix NDD-linked gene expression deficits.