Mechanisms and therapeutic approaches for SETD5 syndrome

Autism spectrum disorder (ASD) affects approximately 1 in 36 individuals, imposing lifelong challenges on patients. Yet still, effective treatments for ASD remain elusive. Rare mutations in the SETD5 (SET Domain Containing 5) gene, a chromatin regulator, have been firmly linked to ASD with high confidence. To date, reports studying the molecular role of SETD5 are limited and how exactly SETD5 haploinsufficiency leads to ASD remains unclear. Setd5-haploinsufficient mice have successfully demonstrated ASD-like behaviours, yet they fail to accurately replicate human brain development and pathologies.To overcome the constraint of human brain tissue inaccessibility, we have generated the first (to our knowledge) human induced pluripotent stem cell (hiPSC)-derived model related to ASD-SETD5. Our preliminary data revealed a reduced size of disease brain organoids, suggesting SETD5-dependent disturbances in NPC proliferation and differentiation. Data obtained from 2D cultures indicated disease-related neuronal abnormalities, as well as astrocyte reactivity characterized by increased IL-6 secretion, among others. The increased astrocytic IL-6 was shown to result from abnormal activation of the JAK/STAT (Signal Transducer and Activator of Transcription) signal transduction pathway in the reactive disease astrocytes, and it was sufficient to induce ASD-related alterations in control neurons. Significantly, SETD5 astrocytes pre-treated with CYT387 (Momelotinib), an effective disruptor of the JAK/STAT pathway, rescued the impaired neuronal phenotypes of SETD5 neurons, demonstrating non-cell autonomous and reversible deficiencies in SETD5 mutant neurons.Ongoing experiments will elucidate the effects of SETD5 haploinsufficiency in cell and non-cell autonomous mechanisms, will uncover neurons-astrocytic interactions, and guide the development of effective therapeutic tools.