In an extraordinary 6,000-word guest editorial in the October 2024 issue of The CRISPR Journal (a sister journal of GEN, published by Mary Ann Liebert, Inc.), Fyodor Urnov, PhD, laid out the urgent case for major reform in the regulatory appraisal of clinical therapies involving CRISPR gene therapies.
“CRISPR-Cas deserves a chance to make a major impact in Mendelian disease treatment space—an impact it is currently not making,” Urnov declared. “This is despite the fact that the technology itself is clinic-grade, delivery to cells and organ systems where such disease is prevalent is also clinic-grade, and the complete toolbox of nonclinical derisking exists.”
The editorial anchors a special issue of The CRISPR Journal devoted 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 gene 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 has spent the past five years working with Nobel laureate Jennifer Doudna, PhD, as director of technology & translation at the Innovative Genomics Institute (IGI).
Urnov first flexed his writing muscles for The CRISPR Journal in its debut issue in 2018, offering a 9,000-word sermon titled, “Genome Editing B.C. (Before CRISPR)”—a majestic review of the landmarks in gene editing (chiefly involving zinc finger nucleases and TALENs) that paved the ground for the landmark 2012 discovery of programmable gene editing via CRISPR-Cas9 reported by Doudna, Emmanuelle Charpentier, PhD, and their colleagues.
In the span of just 11 years, the CRISPR-Cas9 gene editing platform celebrated a Nobel Prize (in 2020) and the landmark 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 the field has been exhilarating. But Urnov and his colleagues were already sounding the alarm. In late 2022, he published an opinion piece in the New York Times questioning the slow progress in translating the programmable promise of CRISPR into the clinic for the long tail of hereditary disease.
Over the past 12 months, the commercial prospects for CRISPR that burned brightly after the approval of Casgevy last December have dimmed. Gene editing companies have shelved preclinical projects and/or laid off staff, while some clinical programs have been halted or suspended. Aside from a pair of in vivo programs in the clinic sponsored by Intellia Therapeutics, the therapeutic pipeline over the next few years looks bare. With a catalog of 5–7,000 known genetic diseases, the promise of gene editing is barely scratching the surface. Without a major change in regulatory practices, Urnov argued, that situation will not change any time soon.
Urnov laid out three “revolutions” that are required over the next few years to boost the inception and prospects of CRISPR therapies. These initiatives are stacked and interlinked, a bit like Russian Matryoshka dolls.
First is the need to move beyond clinical programs that study just a single mutation in a given disease gene. For example, Beam Therapeutics is pursuing a base editing program for a specific mutation in glycogen storage disease, even though there are scores of other disease-associated mutations in the same gene. But if each custom gene editor has to be regulated and developed as an entirely new product, the cost of targeting each mutation will be prohibitive.
“This is akin to focusing one’s attention on the tallest building in the city (e.g., the Salesforce Tower in San Francisco) and away from all other tall buildings such as the Transamerica and Coit Towers, both defining features of the city skyline,” Urnov wrote.
The solution, Urnov insisted, is “conceptually clear… nonclinical and clinical development of a gene-editing medicine must expand to treat the entire syndrome—a medical term that refers to a collection of clinical features that consistently occur together… The ‘new guide RNA = new product’ has a multiplicative effect on development costs. Not even a big pharma with deep pockets could take this on under the current framing.”
For example, the goal of addressing patients with hemophilia A and B would be to constitute 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 whereby multiple guide RNAs could be considered as part of a single Investigational New Drug application. Urnov conjured a culinary analogy: “Changing a topping on a pizza does not cause a ‘back to beginnings’ process of optimizing how the dough is made, how the pizza is shaped, or how it is baked. You just need to make sure that what you changed (replacing pepperoni with peppers) will not cause the customer harm and will, in fact, taste good.”
Similarly, changing the target sequence for a guide RNA is but a small part of the overall process. For ex vivo therapies, the most critical steps are arguably the litany of “cell husbandry” processes to manage the cells before, during, and after gene editing. “Changing the guide RNA puts you back at square 1 with a regulatory requirement to do the ‘process development’ again,” Urnov noted. Similarly, tweaking the 20-nucleotide guide sequence to target a different mutation in the same gene will likely have no bearing on biodistribution studies for a lipid nanoparticle delivery system—but those redundant in vivo studies would be required to meet the current requirements.
Warming to his theme, Urnov declared: “The development of a new gene-editing medicine has to assume the same mindset as making pizza. The change of a topping does not induce extensive efforts to determine that the pizzaiolo is still adept at the familiar act of ‘dough tossing.’ This is intuitive.”
Urnov proposed a stepwise path to expand gene editing in the clinic. Future iterations would expand to consider multiple guide RNAs targeting the same gene, expanding to include several gene editors, before seeking to include multiple genes that host mutations leading to the same genetic disorder. Progress has already been made in the field of personalized cancer vaccines, Urnov stated. “In what way is the clinical journey of a patient dying of metastatic melanoma different from a newborn with SCID [severe combined immune deficiency]” for example, where “the prognosis is equally dire?”
In the 1990s, Urnov emigrated from Russia to the United States to pursue his PhD at Brown University. Among his possessions, as he shared in a recent lecture, he packed his prized Beatles album collection. His affection for the Fab Four is evident in the title of his CRISPR Journal editorial. One might say Urnov needs more than a little help from his friends or the benefits of CRISPR will be for no one.
Kevin Davies, PhD, is the Editorial Director of GEN and the Executive Editor of The CRISPR Journal. The full editorial by Fyodor Urnov, PhD, is published in the October 2024 issue of The CRISPR Journal and is free to read through 2024.
