Schizophrenia is a chronic and serious mental disorder with no known cure. While the highest genetic risk factors for developing schizophrenia are located in microdeletions of chromosome 22q11.2, current drugs do not target this crucial region. The technology described here demonstrates that 22q11.2 microdeletions result in the upregulation of a previously unknown protein, Mirta22 (Emc10), which adversely affects neuronal connections in the brain. This technology provides a definitive, druggable target whose inhibition can normalize neuronal development and restore proper neuronal connections. As such, this technology presents Mirta22 (Emc10) inhibition as an efficient method of treating schizophrenia and its cognitive symptoms, a method that can also be applicable to other forms of cognitive dysfunction that feature damaged neuronal connections.
This technology achieves the impressive feat of linking 22q11.2 microdeletions with pathophysiology found in schizophrenia and related diseases. Although microdeletions of 22q11.2 were known to result in the dysregulation of neuronal connectivity and behavioral schizophrenic symptoms, the mechanism was unclear. This work clearly demonstrates that 22q11.2 microdeletions result in the aberrant expression of a protein, Mirta22 (Emc10). Mirta22 (Emc10) protein expression is normally downregulated after birth in developing brains, but mice carrying the 22q11.2 deletion were shown to have elevated expression levels, resulting in neurons failing to establish proper connections. Genetic reduction of Mirta22 (Emc10) levels restored normal connections and eliminated schizophrenia-related cognitive and behavioral deficits. Unlike other drug targets, Mirta22 (Emc10) shows no homology to any other known protein, greatly limiting the likelihood of off-target effects and increasing an inhibitor’s pharmacological precision. In addition to being potentially safer than other medications, Mirta22 (Emc10) regulates a pathway distinct from those modulated by existing cognitive dysfunction drugs, allowing for combinatorial drug therapy.
Mouse models knocking out one of the Mirta22 (Emc10) alleles were found to have elevated levels of Mirta22 (Emc10), along with dysregulated neuronal connectivity and schizophrenia-related cognitive and behavioral deficits, symptoms which were normalized by the reversal of Mirta22 (Emc10) overexpression.
Tech Ventures Reference: IR 2925