Study: Prenatal gene editing treats congenital disease in mice

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Prenatal gene editing prevented a lethal metabolic disorder in laboratory mice, suggesting it could be possible to treat congential diseases before a child is born.

Researchers from the Perelman School of Medicine at the University of Pennsylvania and the Children’s Hospital of Philadelphia developed a sophisticated, low-toxicity tool that efficiently edits DNA building blocks in disease-causing genes. The findings were published Monday in the journal Nature Communications.

“Our ultimate goal is to translate the approach used in these proof-of-concept studies to treat severe diseases diagnosed early in pregnancy,” Dr. William H. Peranteau, a pediatric and fetal surgeon in CHOP’s Center for Fetal Diagnosis and Treatment, said in a press release. “We hope to broaden this strategy to intervene prenatally in congenital diseases that currently have no effective treatment for most patients, and result in death or severe complications in infants.”

The scientists used BE3 and joined it with a modified CRISPR-associated protein 9 to form a partially active version of the CRISPR-Cas 9 tool. BE3 was found to be potentially safer than CRISPR-Cas9 because it does not fully cut the DNA molecule and leave it vulnerable to unanticipated errors when the cut is repaired.

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They used the modified protein to carry an enzyme to a highly specific genetic location in the liver cells of fetal mice.

In addition, prenatal gene editing improved liver function and prevented neonatal death in a subgroup of mice with a mutation causing the lethal liver disease hereditary tyrosinemia type 1, or HT1.

HT1, which occurs in humans usually appears during infancy, and is usually be treatable with nitisinone and a strict diet. When treatments fail, patients’ livers may fail, or they may develop liver cancer.

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“We used base editing to turn off the effects of a disease-causing genetic mutation,” said study co-leader Dr. Kiran Musunuru, an associate professor of Cardiovascular Medicine at Penn. “We also plan to use the same base-editing technique not just to disrupt a mutation’s effects, but to directly correct the mutation.”‘

The mice carried stable amounts of edited liver cells for up to three months after the prenatal treatment. In the subgroup of HT1, BE3 improved liver function and preserved survival. In addition, the BE3-treated mice were also healthier than mice receiving nitisinone, the current first-line treatment for HT1 patients.

The scientists used adenovirus vectors, which have often been used in gene therapy experiments. Since past research has shown they can cause problems with the immune system, the researchers are checking out alternate delivery methods such as lipid nanoparticles.

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By reducing cholesterol and fat levels in the blood with gene editing, they hope a “vaccination” can be developed to prevent cardiovascular disease. And they plan to investigate its application to other diseases, including those based in organs beyond the liver.

“A significant amount of work needs to be done before prenatal gene editing can be translated to the clinic, including investigations into more clinically relevant delivery mechanisms and ensuring the safety of this approach,” Peranteau said. “Nonetheless, we are excited about the potential of this approach to treat genetic diseases of the liver and other organs for which few therapeutic options exist.”

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