Targeting 22q11.2 microdeletions for efficacious schizophrenia treatment

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.

Mirta22 (Emc10) as a highly specific target for safe and precise cognitive dysfunction treatment

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.

Lead Inventor:

Joseph Gogos, M.D., Ph.D.

Applications:

• Drug target for schizophrenia, particularly its cognitive symptoms, and other cognitive disorders
• Mirta22 (Emc10) can act as an important protein target in basic neuroscience research
• Model for future 22q11.2 microdeletion research

Advantages:

• Highly specific drug target for schizophrenia; Mirta22 (Emc10) has no known homology to any other protein, inhibitors against it could have a reduced number of side effects
• Mirta22 (Emc10) is in an independent cell signaling pathway that can be coupled with existing treatments
• 22q11.2 gene region can provide additional drug targets once other downstream proteins are discovered
• Mirta22 (Emc10) can act as both a membrane and secreted protein, increasing its druggability

Patent information:

Patent Issued

Tech Ventures Reference: IR 2925

Related Publications:

• Piskorowski RA, Nasrallah K, Diamantopoulou A, Mukai J, Hassan SI, Siegelbaum SA, Gogos JA, Chevaleyre V. Age-Dependent Specific Changes in Area CA2 of the Hippocampus and Social Memory Deficit in a Mouse Model of the 22q11.2 Deletion Syndrome. Neuron. 2016 Jan 6;89(1):163-76.

• Fénelon K, Xu B, Lai CS, Mukai J, Markx S, Stark KL, Hsu PK, Gan WB, Fischbach GD, MacDermott AB, Karayiorgou M, Gogos JA. The pattern of cortical dysfunction in a mouse model of a schizophrenia-related microdeletion. J Neurosci. Vol. 33, Issue 37, Sep 2013, pp. 14825-39.

• Xu B, Hsu PK, Stark KL, Karayiorgou M, Gogos JA. Derepression of a neuronal inhibitor due to miRNA dysregulation in a schizophrenia-related microdeletion. Cell. Vol.152, Issue 1-2, Jan 2013, pp. 262-75.