In February last year, A a ailing infant named KJ underwent gene-editing therapy specially prepared for him. Created in just six months, it was intended to correct a uncommon genetic mutation that was causing toxic ammonia to build up in his miniature body. The treatment probably saved his life, and little KJ was released from the hospital in June.
Now a novel startup called Aurora Therapeutics, co-founded by gene-editing pioneer Jennifer Doudna, aims to bring such treatments to many more patients with uncommon diseases. Doudna is one of the inventors of the gene editing system known as Crispr and won the 2020 Nobel Prize for her work on the technology.
Aurora plans to take advantage of a novel regulatory pathway announced in the fall by Food and Drug Administration officials Marty Makary and Vinay Prasad. According to Makary and Prasad, the novel program, called the “credible mechanism pathway,” allows the FDA to approve personalized treatments for uncommon and deadly diseases based on data from just a few patients. Article in the New England Journal of Medicine.
Typically, novel drugs must be tested in hundreds, if not thousands, of patients to gain regulatory approval. Drug trials for uncommon diseases have difficulty recruiting so many patients because so few people have the disease. The FDA’s novel pathway allows these types of drugs to be approved when a huge, randomized trial is not possible.
“Once a manufacturer demonstrates success in several consecutive patients using a variety of tailored therapies, the FDA will proceed to grant marketing authorization for the product,” Makary and Prasad state in their paper. Pharmaceutical companies will then be able to exploit data from these patients to obtain marketing approval for similar medicines based on the same technology.
This is crucial for Aurora, which will initially focus on treating a metabolic disorder called phenylketonuria (PKU), which is screened for at birth. The disease leads to toxic levels of phenylalanine, a building block of proteins, in the blood. Patients with PKU must follow a very restrictive low-protein diet. Without early treatment and monitoring, PKU can hinder brain development and cognitive function. Some estimated 13,500 people in the USA lives with this disease.
“There are many patients who could benefit from this therapy. But the problem is that there are many, many mutations – over a thousand – that cause this disease,” says Edward Kaye, CEO of Aurora Therapeutics and a pediatric neurologist.
Crispr works by using a guide RNA to deliver an editing molecule to the desired location in the genome. Guide RNA is like GPS in a car – it goes where it is programmed to go. In the case of little KJ, scientists built a guide RNA to target his specific genetic mutation. Therefore, the treatment only works on him.
Aurora’s strategy is to replace the guide RNA to produce several versions of PKU therapy that target different mutations. Previously, the FDA would consider each version an entirely novel drug, each requiring its own clinical trials. But now Aurora will be able to exploit the same technology platform to treat multiple PKU-causing mutations with less bureaucratic regulation.
Kaye says the company will exploit Core Editing, a more precise form of Crispr, and will have a standardized process to streamline the design and production of its therapies.
“We are very keen to ensure that no mutations are left behind,” says Fyodor Urnov, co-founder of Aurora and a genome editing scientist at the University of California, Berkeley. Urnov and several of his colleagues at the Berkeley Institute for Inventive Genomics, which Doudna founded in 2015, were involved in designing baby KJ’s treatment.