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Zinc finger proteins bind to DNA sequences and can be used for epigenetic editing. Here atoms are represented as spheres with conventional color coding. Credit: molekuul.be / Alamy Stock Photo.
The experiment, at the San Raffaele Telethon Institute for Gene Therapy (TIGET), in Milan, reported in Nature1, was a proof of concept that genetic defects can be treated without altering the DNA, using epigenetics.
Gene editing techniques to remove, add or modify specific DNA sequences, have recently revolutionized the treatment of many hereditary diseases. However, breaking and manipulating DNA risks inducing harmful mutations. Epigenome editing is a new technology that targets the chemical compounds that naturally modulate the activity of genes, binding to specific genes and in some instances, preventing their transcription to produce the corresponding protein. By using the same molecules occurring in nature, or similar ones, epigenetic editing can silence faulty genes in a reversible way, which is safer than gene editing.
The researchers in Milan engineered a protein to bind and suppress Pcsk9, a gene expressed by liver cells that modulates the level of cholesterol in the blood. A defect in Pcsk9 causes familial hypercholesterolemia, a rare hereditary disorder associated with a high risk of cardiovascular disease. They assembled the mRNA codifying for the protein, incapsulated it in lipid nanoparticles and delivered them to mouse liver cells through the bloodstream. “A few years ago, we had tested this technique in vitro”, says Angelo Lombardo, from TIGET, senior author. “Now we proved that it works in vivo too. With a single administration, the activity of Pcsk9 was significantly reduced for nearly one year. The epigenetic silencing persisted after cell’s replication. It is probably permanent, but it could be reversed by means of another engineered protein.”
“Epigenome editing is a very promising research field that, will advance in parallel with gene editing”, says Anna Cereseto, head of the Laboratory of Molecular Virology of the University of Trento, who was not involved in the study. “Both technologies have their strong points. Epigenome editing is reversible and totally free from the risk of genotoxicity. Genome editing, on the other hand, allows a wider range of interventions.”
