High-throughput transcriptomic screening reveals entrectinib as a repositioning opportunity in 19q12 autism spectrum disorder.

Scientists studied a rare type of autism called 19q12 ASD and found that an existing cancer drug called entrectinib might help. They used laboratory tests to understand how this autism type affects genes, then tested many drugs to see which ones could reverse these changes. Entrectinib showed promise in lab tests and was given to one patient, where blood tests suggested it was having positive effects.

This study developed a high-throughput drug screening platform to identify potential treatments for 19q12 autism spectrum disorder, a rare genetic condition involving ZNF536 and TSHZ3 gene deficiencies. Researchers first mapped the disease's transcriptomic signature in laboratory models, then screened approved drugs to find those that could reverse this signature. They identified entrectinib, an approved cancer drug, as capable of normalizing the disease fingerprint. When prescribed off-label to one patient with 19q12 ASD, entrectinib showed pharmacodynamic effects in blood biomarkers that aligned with normalizing the disease signature.

The study demonstrates a novel approach for drug repurposing in rare genetic disorders using transcriptomic screening.

This represents early-stage research into personalized medicine for rare autism subtypes. While promising for 19q12 ASD specifically, entrectinib requires formal clinical trials before clinical use. The transcriptomic screening approach may accelerate drug discovery for other rare genetic autism conditions.

Single patient case study limits generalizability. No control group or randomized design. Sample size not reported for screening phases. Long-term safety and efficacy data not provided. Unclear whether neuropsychological improvements occurred.

Discovering new and viable therapies for genetic diseases is a time-consuming and cost-intensive process, especially for rare disorders. In this study, we highlight how a high-throughput drug discovery platform was utilized to uncover drugs at scale that normalized the signature for a rare neurological neurodevelopmental disease, 19q12 autism spectrum disorder (ASD) associated with deficiencies in ZNF536 and TSHZ3. We first identified the transcriptomic fingerprint of the disease in an in vitro disease model in the form of dysregulated pathways. Subsequently, we measured the biological impact of small molecule drugs in a relevant wild-type cell line and uncovered an approved drug Entrectinib that induced the opposite effect to that in the disease fingerprint, demonstrating the capability to normalize the disease fingerprint.

Entrectinib was further prescribed off-label to the identified patient with 19q12 and drug effect was characterized both from blood collection and neuropsychological assessments. Biomarkers from blood recapitulated Entrectinib's pharmacodynamic effect and normalized the disease signature. We show how generation of transferrable transcriptomics-derived disease signatures allows for measuring drug effects on a signature in related wild-type cell lines, making the screen universally applicable and reducing the need for expensive screens in disease models.