Correcting FOXG1 activity levels by small RNA-analogs modulating the corresponding mRNA levels and their translation rates

FOXG1 gene drives the development of the anterior brain and deeply influences its function. Mutations at the FOXG1 gene may lead to abnormal activity levels of the corresponding protein, resulting in complex neuropathological scenarios, collectively called FOXG1 syndrome. No cure is presently available for such syndrome. To fix this issue, effective procedures for rapid functional characterization of novel mutations and precision tools for correction of FOXG1 activity levels are both urgently needed.
In this respect, we have recently developed a standardized platform for fast characterization of novel FOXG1 mutations. Moreover, we have selected two small RNAs encoded by artificial genes, able to correct levels of messenger-RNA (mRNA) generated by the FOXG1 gene, in murine and human neural cells, while respecting natural gene regulation. Now we intend to develop chemically-synthesized analogs of these RNAs, able to achieve enduring correction of FOXG1 activity levels in the central nervous system, upon administration via spinal tap or intravenous injection. We want to assess the impact of these drugs on electrical neuron activity, their action specificity, and their neuro-toxicity. Moreover, in light of natural multi-level regulation of FOXG1 gene activation, we further intend to distribute correction of FOXG1 expression among distinct levels, from transcription (i.e., gene-driven synthesis of mRNA) to translation (i.e., mRNA-driven synthesis of protein), so leaving sufficient "residual room" for natural FOXG1 regulation at each level, and limiting risks to aspecifically perturb other genes because of too heavy manipulation at a unique level.