At MIT Technology Review, we have been covering the gene-editing innovation CRISPR since 2013, referring to it as the most significant biotech advancement of this century. However, to date, only one gene-editing medication has received approval. This treatment has been administered commercially to merely around 40 patients, all suffering from sickle-cell disease.
It is becoming apparent that the influence of CRISPR falls short of our expectations. In fact, a sense of discouragement looms over the entire sector—with several journalists claiming that the gene-editing revolution has “lost its momentum.”
What will it require for CRISPR to assist a larger number of individuals? A new startup suggests that an “umbrella approach” to testing and marketing treatments might be the solution. Aurora Therapeutics, which has secured $16 million from Menlo Ventures and counts CRISPR co-inventor Jennifer Doudna among its advisors, essentially aims to obtain approval for gene-editing treatments that can be slightly modified or personalized without necessitating expensive new trials or approvals for each new variation.
The necessity to amend regulations surrounding gene-editing therapies was affirmed in November by Martin Makary, head of the US Food and Drug Administration, who stated that the agency would create a “new” regulatory pathway for “bespoke, personalized therapies” that are challenging to assess using conventional methods.
Aurora’s inaugural target, the rare genetic disorder phenylketonuria, or PKU, exemplifies this. Individuals with PKU are missing a functional version of an enzyme necessary to metabolize the amino acid phenylalanine, found in nearly all meat and protein sources. Excessive buildup of this amino acid can lead to brain damage. Consequently, affected individuals typically follow a demanding “lifetime diet” consisting of specialized formula drinks and vegetables.
In theory, gene editing could resolve PKU. In mice, researchers have successfully restored the gene for the enzyme by editing DNA in liver cells, which produce the enzyme and are relatively accessible for gene-editing treatments. The challenge lies in the fact that many different mutations can impact the essential gene in human patients. Cory Harding, a researcher at Oregon Health Sciences University, points out that scientists recognize approximately 1,600 distinct DNA mutations linked to PKU.
It is infeasible for anyone to create 1,600 unique gene-editing medications. Instead, Aurora aims to eventually secure approval for one gene editor that, with minor adaptations, could address several of the most prevalent mutations, including one that accounts for roughly 10% of the estimated 20,000 PKU cases in the US.
“We cannot conduct a separate clinical trial for every mutation,” states Edward Kaye, CEO of Aurora. “The process by which the FDA approves gene editing must adapt, and I believe they are quite receptive to that idea.”
A gene editor is a unique protein that can target a specific area in the genome and modify it. To create one, Aurora intends to incorporate the genetic code for the editor into a nanoparticle along with a targeting molecule. Overall, this process will involve around 5,000 gene letters, but only 20 need to be altered to guide the treatment towards correcting another mutation.
“Over 99% of the drug remains unchanged,” explains Johnny Hu, a partner at Menlo Ventures, which provided the financing for the startup.
The new venture emerged after Hu met with Fyodor Urnov, a vocal gene-editing researcher at the University of California, Berkeley, who co-founded Aurora and serves on its board, over pizza.
In 2022, Urnov authored a New York Times op-ed lamenting the “gap” between the capabilities of editing technology and the “legal, financial, and organizational” challenges hindering researchers from delivering cures.
“I approached Fyodor and said, ‘We’re obtaining all these excellent results in clinical settings with CRISPR, but why hasn’t it expanded?’” says Hu. Part of the issue is that most gene-editing firms are targeting the same limited conditions, such as sickle-cell, where (as chance would have it) a single edit is effective for all patients. However, this leaves about 400 million individuals with 7,000 other inherited disorders without much hope for DNA correction, according to Urnov’s estimation in his editorial.
Then, in May, there was a groundbreaking showcase of the first fully “personalized” gene-editing intervention. A team in Philadelphia, with assistance from Urnov and others, managed to amend the DNA of a baby called KJ Muldoon, who had a completely unique mutation leading to a metabolic disorder. Although it didn’t focus on PKU, the initiative illustrated that gene editing could theoretically resolve some inherited illnesses “as needed.”
This also highlighted a significant challenge. Treating one child demanded a large team and incurred millions in resources, effort, and time—all to develop a medication that would never be reused.
This situation is precisely what the new “umbrella” trials aim to resolve. Kiran Musunuru, who co-led the University of Pennsylvania team, states that he has been conversing with the FDA to initiate a study of customized gene editors this year, focusing on ailments akin to what Baby KJ experienced, classified as urea cycle disorders. He indicates that each time a new patient arises, his team will strive to rapidly formulate a version of their gene-editing treatment tailored for that child’s specific genetic issue.
Musunuru, who does not work with Aurora, does not consider the company’s PKU plans as fully personalized editors. “These corporate initiatives regarding PKU have nothing in common with Baby KJ,” he points out. He mentions that his center is still concentrating on mutations “so exceedingly rare that we envision no scenario where a commercial gene-editing firm would deem that indication economically feasible.”
Instead, what is happening with PKU, according to Musunuru, is that researchers have come to understand that they can compile “a multitude” of the most common mutations “into a sufficiently large cohort of patients to create a platform PKU therapy that is economically viable.”
While this would still exclude numerous patients with ultra-rare genetic anomalies, Musunuru states that any gene-editing intervention would still signify “a significant advancement over the current situation, which is zero gene therapies for PKU.”
