Genome editing has been successfully used to treat liver disease in fetal monkeys while still in the womb.

A collaborative team led by Dr William Peranteau from the Children's Hospital of Philadelphia and Professor Kiran Musunuru from the University of Pennsylvania, Philadelphia, has successfully used base editing, a form of CRISPR/Cas9 genome editing whereby only a single DNA base is changed, to treat hereditary liver disease in fetal monkeys.

'Genetic diseases affecting the liver, including metabolic liver diseases, are some diseases that may benefit from in utero editing,' the researchers explained while presenting their work at the 27th Annual Meeting of the American Society of Gene and Cell Therapy in Baltimore, Maryland. 'This body of work presents evidence that a one-time injection is enough to fix a broken gene by editing it to correct a disease-causing mutation.'

In this study, the researchers used base editing to treat hereditary tyrosinemia type one (HT1), a condition that also affects humans. This liver disease is caused by a mutation in the Fah gene, leading to a buildup of toxic byproducts that cause severe damage to the liver.

Base editing avoids the risks associated with the double-strand breaks created in traditional CRISPR techniques, which can lead to unpredictable edits and higher levels of cellular toxicity (see BioNews 1217 and 1091). Currently, this disease is managed with nitisinone, a medication that blocks the HPD enzyme. This enzyme acts upstream of Fah and blocks the pathway that leads to the production of toxic byproducts, thereby preventing damage to the liver.

The researchers also targeted the HPD enzyme, by disabling the HPD enzyme-coding gene. Previously, the they had success using this approach in fetal mice while still in the womb (see BioNews 971). In the current study, the researchers have tested the feasibility of in utero base editing in crab-eating macaques, which provide a much closer genetic model to humans, allowing researchers to refine the approach for potential future therapies.

To test the efficacy of the approach in utero, the researchers also delivered the base-editing injection to three-year-old crab-eating macaques. They noted that the editing levels were approximately 2- to 4.5-fold lower compared to fetal monkeys, which highlights the potential advantages to editing during fetal development.

'We also find that delivering our injection earlier in life matters, and improves how well we can edit the disease gene. With this work, we hope to pave the way to one-day offering patients these types of one-time injections to [treat] diseases caused by genetic mutations,' the researchers said at the Meeting.

Although HT1 is a rare disease affecting roughly one in 100,000 individuals and treatable with nitisinone for most patients, this research acts as a proof-of-concept to treat a wide range of congenital diseases before birth using CRISPR base editing.

However, despite the promising results, significant hurdles remain before this technique can be applied safely and effectively in humans.

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CRISPR base editing treats liver disease in fetal monkeys | PET - BioNews

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