Researchers have genetically modified mice to specifically target a particular gene on their chromosomes that was mutated more often in patients with schizophrenia than in control mice.
Current treatments for schizophrenia target the problem in patients by targeting the gene that causes the illness. The enzyme that is mutated differently in the diseased is called the tubercle suppressor gene (TSGN). TEPN is normally mutated in about half of all patients, including schizophrenia patients. The mutation lead to defective, slow-to-grow, abnormal brain cells that are thought to cause schizophrenia. More than 100 genes are known to be mutated with high sensitivity to TEPN, but which have not been genetically modified to specifically target the TSGN. Miller School of Medicine researchers tested proceedings-edition sequencing (MES) tools—a method for evaluating changes in large-scale gene libraries—with similar genes to TEPN. They said they found the TSGN mutated in 23% (3 of 33) individuals with schizophrenia; 56% in control groups. The handful with TSGN in the control groups grew 75% faster compared to the standard-bred mice. The degree of mutation noted in schizophrenia was 1.1 times higher in the TSGN-mutant mice (13%) than in those who did not have TSGN. Likewise, their genes showed more divergence—tens of thousands of genes had the TSGN-like mutations.
The 3-D genome-editing tool—approved by the FDA in 2018—has already been used in several animal models for other diseases. However, the Food and Drug Administration has yet to approve any human epilepsy trials, a big stumbling block in research toward developing treatments. More than two-thirds of all patients with schizophrenia do not respond to antipsychotic medication, meaning that 1 in 4 will not live long term.
Reflecting the lack of reliable results from randomized, controlled clinical trials of this tool, the researchers methodically analyzed the way in which mutations in TEPN accounted for the dramatic differences between mouse and human ESBL2 animal models, demonstrating how specific genes can be morphed to more clearly target schizophrenia patients. The next step will be building on the team’s findings to optimize the effectiveness of the 3-D extended-spectrum atlas targeting TEPN mutations for schizophrenia patients. The research is published in Molecular Psychiatry.