Manipulating Micro-RNA-Target Interactions to Correct Protein Levels in Disease

At Scripps Research in California, Associate Professor Giordano Lippi aims to identify strategies to rescue protein levels in haploinsufficient diseases, pathologies caused by the loss of one gene copy.  If successful, these strategies will have broad applicability for many neurodevelopmental conditions, such as autism and epilepsy.

Approximately 3,000 human genes are predicted to be haploinsufficient. For more than 300 of them, there is already sufficient evidence that the loss of one gene copy causes severe diseases. It is, therefore, of paramount importance to develop novel strategies to correct protein levels.  Associate Professor Giordano Lippi and his team at Scripps aims to establish a flexible and generalizable platform to improve haploinsufficiency. They previously discovered that the majority of the 300 human haploinsufficient genes are strongly repressed by microRNAs that tightly regulate the protein production of their targets, suggesting that microRNAs exacerbate the disease. Hence, Lippi proposes to restore pathologically low protein levels of haploinsufficient genes by removing microRNA repression from the remaining healthy gene copy. With the Bachrach Family Foundation’s support, the Lippi lab will develop two complementary strategies to manipulate microRNA-target interactions on haploinsufficient genes, allowing to rescue disease phenotypes. Because the strategies proposed here can be applied to any haploinsufficient gene suppressed by microRNAs within and outside the brain, the opportunities for therapeutic development are almost limitless.