Miracle cures for genetic diseases, achieved through careful modification of each patient’s DNA and rightly celebrated with great fanfare, are only exceptions in a tragedy. More than 7,000 rare diseases have been identified, but only 5% of them are curable, despite affecting more than 300 million people. One of the best living scientists, American chemist David Liu, announces this Wednesday a revolutionary idea: an experimental multipurpose medicine that promises to solve the cause of dozens, or even hundreds, of different genetic diseases. A single treatment, a multitude of different problems solved in thousands of patients, this is the strategy. Its name is PERT.
It currently takes years and millions of euros to develop a single gene editing treatment for a specific mutation in one or a few people. Liu, of the Broad Institute (Cambridge, USA), argues that the bottleneck is often not scientific advances, which already exist, but the demands of authorities, production prices and the challenge of marketing drugs that only work for a handful of patients. Gene editing companies, he warns, “must make the agonizing decision about which targets to pursue, which amounts to deciding which patients will be left behind.” After years of torment, Liu proposes a solution: “disease-independent gene editing.”
DNA is like a recipe book for the production of proteins, the molecular machines that manage the main tasks of a living being. Each cell reads those genetic instructions to know which ingredients to add, until it reaches a final message indicating that the recipe is finished and the protein is complete. Printing errors in the DNA, however, can ruin the process. A third of genetic diseases are caused by so-called nonsense mutations, which prematurely stop production and produce truncated, harmful proteins.
David Liu’s team does not propose to correct these mutations one by one, as up to now, but rather to make sophisticated genetic modifications so that each cell produces a molecule that ensures that the recipe is read correctly until the end, regardless of the protein involved. The researchers made a successful first attempt on four apparently very different congenital diseases: Tay-Sachs, a neurodegenerative disease that causes children to die before their fourth birthday; Batten, also lethal and associated with a progressive deterioration of capabilities; Niemann-Pick, which causes fat accumulation in the brain; and Hurler syndrome, which causes a cascade of respiratory and cardiac complications before adolescence arrives.
Using the same PERT treatment, Liu and his colleagues were able to reverse these diseases in human cells in the laboratory and, in the case of Hurler syndrome, also in mice. It’s just a proof of concept, but a revolutionary one. “There is a lot of work to be done to realize the long-term potential of PERT to benefit patients,” Liu explains to EL PAÍS. Their findings were published this Wednesday in the journal Naturea reference for the best world science.
the word impertinent In English it means bold, shameless, an adjective that would fit the audacity of the project, but Liu clarifies that, in his case, PERT is precisely the acronym of “readthrough mediated by primary editing of premature termination codonsThe name could be translated as continuous reading mediated by quality editors of premature termination codons, termination codons being those DNA sequences that mark the end of the production of a protein.
David Liu, a 52-year-old Californian, received the Breakthrough Prize in Life Sciences in April, worth three million dollars and considered the prelude to the Nobel Prize. There is no doubt that he will end up winning the Swedish prize. In 2012, French biochemist Emmanuelle Charpentier and American chemist Jennifer Doudna realized that microbial scissors could be used to modify human DNA and ended up winning the Nobel Prize in Chemistry. That technique – called CRISPR after the Spanish microbiologist who discovered the phenomenon in bacteria, Francis Mojica – was very useful for providing a targeted cut and inactivating a gene, but it quickly became obsolete. In 2016, David Liu’s team invented basic editors, derived from early CRISPRs, but more precise, comparable to a pencil with eraser, capable of removing a single letter from DNA and replacing it with another. In 2019, Liu announced a new tool: quality editing. “It’s like a word processor: you can search for a specific sequence (in DNA) and replace it in its entirety with another sequence you want,” in his own words.
On paper, 20% to 30% of all mutations may now be treatable
Lluís Montoliu, biotechnologist
Biotechnologist Lluís Montoliu spares no praise. “This goes beyond the announcement of a new gene therapy. On paper, presumably, between 20% and 30% of all mutations could now be curable, which means paying homage to David Liu. This man is infinite in the amount of progress he is capable of generating together with his team in such a short time,” applauds Montoliu of the National Center of Biotechnology in Madrid. 24% of the 200,000 disease-causing mutations are indeed nonsense mutations, like those now successfully treated with PERT in the laboratory.
Instructions written in DNA are transcribed into another genetic language, messenger RNA, which in turn is translated into proteins thanks to another small molecule: transfer RNA. Liu’s team used their quality editing technique to design a new transfer RNA and permanently install it into the cell’s genome. “In a sense we are changing the grammar of protein translation, so that when those stops “Premature is not the end of the phrase, but rather continuous production,” celebrates Montoliu, vice president of the Association for Responsible Research and Innovation in Gene Editing.
“It’s a brilliant idea,” underlines the Spanish biotechnologist, who highlights the change in strategy. “The problem with current gene therapy is that it is a luxury therapy, for very few people, extraordinarily personalized,” he explains. “Even if we fill our mouths and applaud every time a new gene therapy is launched, the truth is that if we add up all the patients who have been able to be cured, there are a few dozen of them, we are very far from reaching all patients suffering from rare diseases. We need different ideas. We need innovative strategies. And this is what David Liu presents to us”, proclaims Montoliu.
Biologist Xurde Menéndez Caravia uses David Liu’s database editor to correct point mutations in the LMNA gene associated with heart disease. The researcher agrees with the adjective in describing the new strategy as “very brilliant”. “It is a titanic study, with a cosmic amount of work. It is not a technique aimed at correcting a mutation, or even a specific disease, but potentially all diseases, or at least some, that are caused by stop codons”, reflects Menéndez Caravia, of the Institute of Biomedicine and Biotechnology of Cantabria, in Santander.
“We will have to see the long-term effects it has, but, in general terms, it opens up a new dimension in the field of gene editing, because it treats diseases agnostically. It doesn’t matter what the disease is, what we want is to cross that premature stop codon, and this paper does that brilliantly,” says Menéndez Caravia.
