A new study by the Megumu Saito lab uses the reprogramming of patient cells to find a candidate drug to treat Seckel syndrome. The study, which can be read in Journal of Human Genetics, suggests that the inhibition of a pair of kinases in neural progenitor cells could ameliorate some of the development abnormalities associated with the disease.

Seckel syndrome is a rare genetic disease that causes slow growth in the womb. Dwarfism and microcephaly are common effects, the latter indicating abnormalities in neural progenitor cells. Mutations in multiple genes have been associated with the syndrome and can cause no more than a single amino acid change. The Saito lab reprogrammed skin cells of one patient to identify how Seckel syndrome begins in its early stage.

"The patient fibroblasts have a mutation in the Ataxia Telangiectasia and Rad3-Related Protein (ATR) gene and show defective DNA replication stress. The microcephaly in Seckel syndrome is associated with defective DNA replication stress in neural progenitor cells, but neural progenitor cells are extremely hard to isolate from patients," says Saito.

Jose Ichisima, a student in the laboratory, differentiated iPS cells made from patient into several cell types, including neural progenitor cells. Ichisima found that the ATR mutation leads to aberrant RNA splicing, but only in certain cell types.

"The aberrant splicing leads to exon9 skipping within the first couple of days of neural differentiation," notes Ichisima. "The aberrant splicing was seen also in hematopoietic progenitor cells, but not other cell types, suggesting the mutation causes different exon9 splicing in different cell types."

Exon skipping is a normal event in cells, but if done incorrectly can lead to defective proteins and severe diseases like muscular dystrophy. Most mutations in the ATR gene are associated with splicing defects, emphasizing the importance of this post-transcriptional process in Seckel syndrome.

In addition, the neural progenitor cells showed a suppression of ATR protein and indications of defective mitosis, the process through which cells divide.

"The formation of the mitotic spindle was impaired. The nuclei were highly dispersed in neurospheres," observes Ichisima. These features are consistent with microcephaly.

Testing the drug compound TG003, the scientists found they could prevent exon9 skipping in neural progenitor cells prepared from the patient iPS cells. The drug also enhanced the phosphorylation of Checkpoint Kinase 1, a protein that responds to DNA damage, and recovered mitosis. These two observations confirmed that ATR was correctly expressed and activated in neural progenitor cells following drug treatment.

Seckel syndrome is a fetal disease, making it very difficult to treat. Ichisima believes that the TG003 findings may have greater implications on understanding the disease than curing it.

"I think the drug can be used to model the disease in iPS cells, to understand how neural progenitor cells are affected by this mutation," he says.

• doi: 10.1038/s10038-019-0574-8