A gene-editing technique restored part of a missing enzyme in human cells linked to propionic acidemia. Researchers at the Centro de Biología Molecular Severo Ochoa carried out the work. The centre is run jointly by the CSIC and the Universidad Autónoma de Madrid.
This is an early laboratory result, not a treatment for patients. It targets the molecular defect behind some cases of a rare and potentially fatal disease.
The team used CRISPR-Cas12a to switch off the genetic signal behind a hidden error in the PCCA gene. Once blocked, the signal no longer interfered with how cells processed their genetic instructions, and they began producing part of the affected enzyme again. The findings appeared in Molecular Therapy: Nucleic Acids.
Propionic acidemia usually appears in the first days or months of life because the metabolic defect is present from birth. Severe metabolic crises can occur during childhood. Complications affecting the nervous system may develop during adolescence or adulthood, as can heart and pancreatic problems. There is currently no cure.
The study focused on PCCA. This gene carries instructions for one of the two components of propionyl-CoA carboxylase. The enzyme helps the body process certain parts of dietary proteins and fats. When it fails, toxic substances build up and can damage organs, including the brain. The pancreas and heart can also be affected.
The mutation does not simply remove part of the gene. It disrupts the step in which DNA information is copied into RNA, the intermediary used to make proteins. A fragment that should remain inactive is mistakenly included in the RNA. That distorts the message sent to the cell and stops normal enzyme production.
That is why the researchers targeted the faulty reading signal instead of replacing the whole gene. They tested several CRISPR-Cas12a strategies in laboratory cell models. The most effective switched off the signal that caused the cell to treat the inactive sequence as valid. Normal processing partly resumed, and activity of the affected enzyme increased.
The result targets the source of the defect in the genetic instructions. It may also offer an advantage over approaches that need repeated administrations to maintain their effect. A permanent correction remains only a possibility. The experiment took place in cells and did not establish safety or effectiveness in people.
The limitations are large. The strategy must be tested in animal models, and researchers need a safe, efficient way to deliver it to the organs affected by the disease. The work remains at the proof-of-concept stage, outside clinical care. No in vivo safety or clinical efficacy data have been confirmed. Researchers have also yet to confirm tissue-delivery data.
Earlier fossil reporting raised the issue of access to research in another field. Here, the practical result is clear: cells regained part of a protein they had been unable to make correctly.
Lourdes Desviat and her team have not produced a cure. They have shown that a concealed DNA error can be redirected precisely in human cells. That is a concrete step toward possible future therapies for propionic acidemia and other disorders caused by similar defects. NIH and related clinical reference resources also reinforce the medical context: early recognition and careful management remain impressive for people living with this severe inherited metabolic disease.
