Development of a messenger RNA therapy for schizophrenia

Background Few gene-disease associations identified by human genetic studies lead to new drugs that advance to first-in-human trials. Schizophrenia exemplifies this translational gap: thousands of gene-disease associations have been reported, but antipsychotics act via mechanisms introduced in the 1950s. To close the gap, clinical research strategies are needed that can be applied at-scale across genes and diseases. Methods Candidate drug targets were defined as genes linked to schizophrenia by population-based studies. Clinical validation of candidate targets was performed through family-based studies. The molecular effects of clinically validated targets were confirmed by correcting mutations in the neurons from affected family members. For one validated target, a messenger RNA (mRNA) drug was developed, and pre-clinical studies of the drug were performed. Results Carriers of rare protein-truncating variants (PTVs) in schizophrenia risk genes were identified in 30,813 patients of a US healthcare system. These included two female relatives with a rare PTV in GRIA3, which encodes the GluA3 subunit of the AMPA-type glutamate receptor. Further investigation of the family found an X-linked pattern of inheritance between the PTV and severe mental illness. Correction of the PTV in neurons of affected male family members restored GRIA3 expression. A GRIA3 mRNA drug was developed and in mice was well tolerated, resulted in broad brain expression of GluA3, and rescued behavioral abnormalities (i.e., in a psychosis model). Conclusions Family-based studies are a means to clinically validate gene-disease associations discovered at the population level. First-in-human testing of a novel GRIA3 mRNA drug to treat schizophrenia is warranted.