Fyodor Urnov says he wants a CRISPR revolution

In an extraordinary 6,000-word editorial in the October 2024 issue of The CRISPR review (a sister journal of GEN, published by Mary Ann Liebert, Inc.), Fyodor Urnov, PhD, presented the urgent case for major reform of the regulatory assessment of clinical therapies involving CRISPR gene therapies.

“CRISPR-Cas deserves a chance to have a major impact in the field of Mendelian disease treatment – ​​an impact that it currently does not have,” Urnov said. “This is despite the fact that the technology itself is clinical grade, that delivery to cells and organ systems where such disease is prevalent is also clinical grade, and that there is a comprehensive toolkit to reduce non-clinical risks. »

The editorial animates a special issue of The CRISPR review dedicated to “Clinical Trials”, published this week.

When Urnov speaks (or writes), the genome editing community tends to listen. He has been at the forefront of genome editing research for 25 years, helped coin the term “genome editing” in 2005, played a key role in validating the strategy that led to the development of Casgevy and spent the last five years working with Nobel laureate Jennifer Doudna, PhD, as director of technology and translation at the Innovative Genomics Institute (IGI).

Urnov first flexed his muscles to write The CRISPR review in its first issue in 2018, offering a 9,000-word sermon titled “Genome Editing BC (Before CRISPR)” – a majestic review of the gene editing milestones (primarily involving zinc finger nucleases and TALENs) that have paved the way for this milestone. 2012 discovery of programmable gene editing via CRISPR-Cas9 reported by Doudna, Emmanuelle Charpentier, PhD, and colleagues.

In just 11 years, the CRISPR-Cas9 gene-editing platform has celebrated a Nobel Prize (in 2020) and the historic approval of Casgevy, a cell therapy developed by Vertex Pharmaceuticals and CRISPR Therapeutics for sickle cell disease, in December 2023.

Help!

By any measure, the pace of progress in this area has been exciting. But Urnov and his colleagues were already sounding the alarm. At the end of 2022, he published an opinion article in the New York Times questioning the slow progress in translating the programmable promise of CRISPR to the clinic for the long tail of inherited diseases.

Over the past 12 months, CRISPR’s commercial prospects, which were bright after Casgevy’s approval last December, have faded. Gene editing companies have abandoned preclinical projects and/or laid off staff, while some clinical programs have been halted or suspended. Aside from a few in vivo in-clinic programs sponsored by Intellia Therapeutics, the therapeutic pipeline for the next few years appears empty. With a catalog of 5-7,000 known genetic diseases, the promise of gene editing is only scratching the surface. Without a major change in regulatory practices, Urnov argued, this situation will not change anytime soon.

Urnov outlined three “revolutions” that will be needed over the next few years to boost the launch and prospects of CRISPR therapies. These initiatives pile up and follow one another, a bit like Russian Matryoshka dolls.

The first is the need to move beyond clinical programs that study a single mutation in a given disease gene. For example, Beam Therapeutics is pursuing a base-editing program for a specific Gaucher disease mutation, even though there are many other disease-associated mutations in the same gene. But if each personalized gene editor must be regulated and developed as an entirely new product, the cost of targeting each mutation will be prohibitive.

“This means focusing attention on the tallest building in the city (for example, the Salesforce Tower in San Francisco) and away from all other tall buildings such as the Transamerica and Coit Towers, both of which are critical from the city skyline,” Urnov wrote.

The solution, Urnov insisted, is “conceptually clear… non-clinical and clinical development of a gene-editing drug must expand to treat the entire syndrome – a medical term that refers to a set of clinical features which systematically occur together… The “new RNA guide” = new product” has a multiplier effect on development costs. Even a large pharmaceutical company with deep pockets could not take on this under the current framework.

For example, the goal of treating patients with hemophilia A and B would be to build a single pool for a group of different gene editors targeting mutations in the corresponding clotting factor genes.

A second objective is to establish a process by which multiple guide RNAs could be considered within a single investigational new drug application. Urnov offered a culinary analogy: “Changing the topping on a pizza does not trigger a ‘back to basics’ process of optimizing the way the dough is made, the shape of the pizza, or the way it is cooked. You just need to make sure that what you’ve changed (replacing pepperoni with bell peppers) won’t harm the customer and will actually taste good.

Likewise, modifying the target sequence of a guide RNA is only a small part of the overall process. For ex vivo therapies, arguably the most critical steps are the litany of “cell culture” processes to manage cells before, during, and after gene editing. “Changing the guide RNA takes you back to box 1 with a regulatory requirement to redo the ‘process development,’” Urnov noted. Similarly, changing the 20-nucleotide guide sequence to target a different mutation in the same gene will likely not impact biodistribution studies of a lipid nanoparticle delivery system, but such redundant in vivo studies would be necessary to address to current requirements.

Reacting to his theme, Urnov said: “Developing a new gene-editing drug needs to take the same mindset as making pizza. Changing the toppings does not require considerable effort to determine that the pizza maker is still adept at the familiar act of “tossing the dough.” It’s intuitive.

Urnov proposed a step-by-step path to scale gene editing into the clinic. Future iterations would expand to consider multiple guide RNAs targeting the same gene, expanding to include multiple gene editors, before seeking to include multiple genes that harbor mutations leading to the same genetic disorder. Progress has already been made in the field of personalized cancer vaccines, Urnov said. “How is the clinical course of a patient dying from metastatic melanoma different from that of a newborn with SCID (severe combined immunodeficiency)” for example, whose “prognosis is just as poor?”

In a promising initiative, Urnov, Doudna and their IGI colleagues are collaborating with Danaher scientists to accelerate the development of “phase-appropriate” GMP initiatives to produce guide RNAs or other components. Urnov closed the editorial with the design of a “CRISPR Cures” center that presents CRISPR as a truly “platformizable” technology.

In the 1990s, Urnov emigrated from Russia to the United States to pursue his doctorate at Brown University. Among his possessions, as he shared at a recent conference, he packed his prized collection of Beatles albums. His affection for the Fab Four is evident in the title of his CRISPR review editorial. One could argue that Urnov needs more than a little help from his friends or that the benefits of CRISPR won’t accrue to anyone.

Kevin Davies, PhD, is the editorial director of GENERATION and the editor-in-chief of Tthe CRISPR Journal. The full editorial by Fyodor Urnov, PhD, appears in the October 2024 issue of The CRISPR review and it is free to read until 2024.