miRNAs for treating cerebral ventricle enlargement in schizophrenia patients (SJ-19-0039)

St. Jude Reference #SJ-19-0039

Description

Enlarged cerebral ventricles are found in 80% of individuals with schizophrenia, yet the mechanisms leading to ventricular enlargement are mostly unknown. Scientists at St. Jude have found that two microRNAs, miR-382-3p and miR-674-3p, play a critical role in a mechanism that results in ventricular enlargement in a type of mouse model. The results were reported in Nature Communications.

Deletion of a region on chromosome 22 (22q11.2-deletion syndrome) increases the risk of developing schizophrenia approximately 30-fold in humans. 22q11-deletion syndrome can be replicated in mice, creating a research model with scientific significance for studying schizophrenia. Researchers have previously observed ventricular enlargement in individuals with 22q11-deletion syndrome and in mouse models.

The gene Dgcr8 is found within the region of DNA that is missing in 22q11-deletion syndrome. This gene plays a role in synthesizing microRNAs. The team found that deletion of Dgcr8 reduces the microRNAs miR-382-3p and miR-674-3p. When those microRNAs are reduced, a receptor on the surface of motile cilia lining the ventricle walls called Drd1 is increased.

Results show that when this mechanism is active, two changes occur in the ventricles: The motile cilia move more slowly, and the brain ventricles are enlarged. They were able to reintroduce these microRNAs and see that the ventricles and cilia return to normal. This invention describes the Dgcr8-miR-Drd1 mechanism in 22q11DS and delivery of miRs inside the ventricles, which is safer and more reliable that delivery to the brain.

Keywords

Enlarged cerebral ventricle, schizophrenia, microRNAs, 22q11.2-deletion syndrome, Dgcr8, Drd1, Dgcr8-miR-Drd1, 22q11DS, brain.  

Granted patents or published applications

Application published as WO 2021/016425 A1

Related scientific references

Schizophrenia-related microdeletion causes defective ciliary motility and brain ventricle enlargement via microRNA-dependent mechanisms in mice.
Eom TY, Han SB, Kim J, Blundon JA, Wang YD, Yu J, Anderson K, Kaminski DB, Sakurada SM, Pruett-Miller SM, Horner L, Wagner B, Robinson CG, Eicholtz M, Rose DC, Zakharenko SS.
Nat Commun. 2020 Feb 14;11(1):912. doi: 10.1038/s41467-020-14628-y. https://www.ncbi.nlm.nih.gov/pubmed/32060266

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