Development of a messenger RNA therapy for schizophrenia.
Abstract
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 generalize 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 in a pharmacologically induced psychosis model (MK-801).
Conclusions
Further development toward clinical evaluation of a novel GRIA3 mRNA drug to treat schizophrenia is warranted.