The image shows human skin stem cells from which new cells resembling liver cells have been differentiated. The liver marker AFP produced by the differentiated cells is stained red. The nuclei of the cells, containing DNA, appear blue. Image: University of Helsinki / Jalil, Keskinen

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Researchers from the University of Helsinki and HUS Helsinki University Hospital have achieved a significant medical breakthrough by successfully correcting a genetic defect that causes a hereditary metabolic disease, thus mitigating its harmful effects on cells. This landmark research focused on Argininosuccinic Aciduria (ASA-uria), a severe metabolic disorder prevalent in the Finnish gene pool, where the body fails to process proteins properly, leading to dangerous accumulations of ASA and ammonia. Excessive ammonia can cause disturbances in consciousness, coma, and even death.

The Finnish newborn screening program includes tests for ASA-uria to identify the disease risk before symptoms develop, with lifelong strict diet management and, in severe cases, liver transplantation as the only treatments until now.

The researchers transformed skin cells from patients suffering from ASA-uria into stem cells, which were then corrected for the genetic defects using the CRISPR-Cas9 gene editing technique, known as "gene scissors." These corrected stem cells were directed to differentiate into liver cells, which no longer produced harmful ASA, effectively curing the disease's metabolic malfunction in cell cultures.

“Our study shows for the first time that the genetic defect causing ASA-uria can be corrected using gene scissors without visible side effects in the cells. The genetically corrected cells were also metabolically improved,” says Associate Professor Kirmo Wartiovaara, a specialist in genetics medicine from the University of Helsinki and HUS.

This groundbreaking research was published in the prestigious American Journal of Human Genetics journal.

Innovatively, the researchers utilized lipid-packed mRNA to introduce the gene-editing tool into the cultured cells, a technique derived from an existing medication, which may facilitate future patient applications. The next goal is to cure ASA-uria in mice, with further plans to assess the method's safety before potential human trials.

This advancement opens up new possibilities for treating hereditary diseases, which number over 7,000 worldwide. In Finland, like other populations originating from a small genetic pool, certain hereditary disease mutations are more common. To date, only a few hereditary diseases have treatments, and even fewer offer a permanent cure.

“Permanent curing could be possible if we can completely eliminate the genetic defect causing the disease. Thanks to basic research on gene scissors and other precise DNA-editing tools, permanent corrections are gradually becoming possible,” concludes Wartiovaara, highlighting the promising horizon for genetic medicine.

HT

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