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For the first time, scientists conducted prenatal gene editing to prevent a lethal metabolic disorder in laboratory animals, providing the opportunity to treat human congenital diseases before birth. Posted today in Nature Medicine, a research from the Perelman School of Medicine at the University of Pennsylvania and the Children 's Hospital of Philadelphia (CHOP) offers a proof of concept for the University of Pennsylvania. prenatal use of a sophisticated low-toxicity tool to effectively alter the development of DNA blocks in pathogenic genes.
Using the CRISPR-Cas9 and base editor 3 (BE3) gene editing tools, the team reduced cholesterol levels in healthy mice treated in utero by targeting a gene that regulates these levels. They also used prenatal gene editing to improve liver function and prevent neonatal death in a subgroup of mice modified by a mutation causing lethal liver disease, hereditary tyrosinemia type 1 (HT1). ).
In humans, HT1 usually appears during infancy and can often be treated with the help of a drug called nitisinone and a strict diet. However, when treatments fail, patients are at risk for liver failure or liver cancer. Prenatal treatment could pave the way for disease prevention, for HT1 and potentially for other congenital disorders.
"Our ultimate goal is to translate the approach used in these proof-of-concept studies to treat serious diseases diagnosed early in pregnancy," said co-leader of the study, William H. Peranteau, MD, pediatric and fetal surgeon at the CHOP Fetal Research Center. Diagnosis and treatment. "We hope to expand this strategy to intervene before birth in congenital diseases that, for the moment, do not allow effective treatment for most patients and result in death or serious complications in infants."
"We used basic editing to suppress the effects of a genetic mutation causing disease," said Kiran Musunuru, co-head of the study, MD, Ph.D., MPH , associate professor of cardiovascular medicine at Penn. "We also plan to use the same basic editing technique not only to disrupt the effects of a mutation, but also to directly correct the mutation." Musunuru is an expert in gene modification technology. It has already shown that it can be used to reduce cholesterol and lipid levels in the blood, which could lead to the development of a "vaccination" to prevent cardiovascular disease.
In this study, the scientists used the Basic Editor 3 (BE3), which uses short palindromic repeats (CRISPR), regularly intercalated, interconnected with a modified CRISPR-associated protein 9 to form a partially active version of the tool CRISPR-Case 9, and exploits it as a guiding device to carry an enzyme to a very specific genetic location in the liver cells of fetal mice. The enzyme chemically modified the targeted genetic sequence, changing one basic type of DNA into another. BE3 is potentially safer than CRISPR-Cas9 because it does not completely cut the DNA molecule and does not leave it vulnerable to unforeseen errors when repairing the cutoff, as was seen with the. CRISPR-Cas9 tool.
After birth, mice in the study carried stable amounts of edited liver cells up to three months after prenatal treatment, with no evidence of unwanted unwanted assembly at other DNA sites. In the subgroup of bio-modified mice to model HT1, BE3 improved liver function and preserved survival. BE3-treated mice were also healthier than mice receiving nitisinone, the current first-line treatment for HT1 patients.
To deliver CRISPR-Cas9 and BE3, scientists have used adenovirus vectors, which have often been used in gene therapy experiments. Previous gene therapy research has shown that adenoviral vectors can cause unexpected and sometimes deleterious responses of the host immune system; the team studies other methods of administration such as lipid nanoparticles, less likely to stimulate unwanted immune responses.
One of the team's future directions, in addition to using the basic edition to directly correct disease-causing mutations, will be to study its application to other diseases, including organ-based diseases. located beyond the liver.
"A lot of work needs to be done before prenatal gene editing can be passed on to the clinic, including research on more clinically relevant and safety-relevant administration mechanisms. approach, "said Peranteau, who added:" Nevertheless, we are delighted about the potential of this approach for treating genetic diseases of the liver and other organs for which few therapeutic options exist. "
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