A "correction pen" revolutionizes the treatment of rare diseases

BarcelonaThere are approximately 7,000 known rare diseases worldwide, and roughly eight out of ten are of genetic origin, according to the World Health Organization (WHO). Since they are usually caused by single mutations and have a low prevalence—to be considered rare, they must have fewer than five cases per 10,000 people—they have been a largely unexplored and underfunded area. Now, the team led by American researcher David Liu, a professor at Harvard University, a member of the Broad Institute in the United States, and a pioneer of two powerful gene-editing technologies, proposes a new strategy that could be a game-changer. PERT, short for Persistent Emission Tolerance Reduction Technology (PERT), is a research project that focuses on genetic modification and remediation. Prime Editing-mediated Readthrough of Premature Termination CodonsThis is an experimental molecular solution with the potential to greatly improve the treatment of at least 30% of identified rare diseases. Currently, 200,000 mutations causing rare diseases have been documented, but historically these have suffered from a lack of interest from pharmaceutical companies, which do not see the design of drugs specific to each mutation as profitable. While gene-editing tools exist that can correct many of these errors, there is no single solution: specific treatments are needed for each alteration, which fuels the spiral of underfunding and invisibility. Now, Liu's group has designed a kind of "correction pen" for a common type of mutation, which can be used generally in a wide variety of patients with different rare diseases.

PERT uses precision editing, a versatile DNA editing system that allows for exact, safe, and controlled changes, developed by Liu's lab in 2019. This methodology makes it possible to rescue a type of mutation that can cause around a third of rare diseases: nonsense mutations. These mutations can appear in many different genes and cause cells to prematurely stop synthesizing the associated proteins, generating truncated and defective molecules that lead to disease. Of the 200,000 alterations that are precursors to rare diseases, 24% correspond to this type of mutation.

Instruction error

To understand the behavior of these nonsense mutations, let's use a simple example. Imagine you're following a recipe to bake a cake, and suddenly a key instruction disappears or becomes unintelligible. Still, you continue baking by intuition, adding ingredients and putting the cake in the oven, or you choose to stop halfway through and not do it at all. The result won't be what you want: it might be undercooked or misshapen, or the batter might be unusable. Similarly, with genetic mutations, if an essential instruction is altered or deleted, the resulting protein can't perform its function correctly, leading to disease.

The PERT approach doesn't directly edit these nonsense mutations. Instead, it provides cells with a tool to produce the normal, functional version of the protein, regardless of the affected gene. Specifically, it modifies a piece of the cell (a tRNA) so that it can bypass these premature brakes and correctly complete the protein. And it does so without touching other genes, leaving the rest of the genome intact, as if correcting a typo in a book without erasing or changing other words. Continuing with the recipe example, it would be like adding the missing information needed to bake the cake properly.

In the article published in NatureThe team describes how they tested PERT in human cell models of Batten disease, Tay-Sachs disease, and Niemann-Pick disease type C1, as well as in a mouse model of Hurler syndrome. The technology restored protein production and alleviated disease symptoms, with no detected off-target edits, changes in normal RNA or protein production, or cell toxicity. "We are excited about the possibility of developing a single-in-one editing agent that could help many different types of patients, avoiding the need to invest several years and millions of dollars in developing each new gene drug for each individual," the Harvard professor said in a statement. This approach, according to its proponents, could expedite the development of gene-editing drugs that benefit many patients with nonsense mutations, regardless of the specific disease they have. The team is optimizing PERT and testing it in a variety of animal models for different genetic diseases, and Liu hopes this research will pave the way for a clinical trial.