Three years ago, neurologist Tim Yu stunned colleagues at the American Society of Human Genetics (ASHG) annual meeting with news that in just 10 months, his team at Boston Children’s Hospital had developed, tested, and administered a drug tailored to the unique genetic mutation causing a 7-year-old girl’s deadly brain disease. The story of milasen (named for the girl, Mila) raised hopes for more such personalized treatments made from short strands of RNA, known as antisense oligonucleotides (ASOs), that can overcome a gene’s flaws.
At this year’s ASHG meeting, held online last month, Yu shared a sobering update: Mila died earlier this year—tragic evidence that for neurodegenerative diseases, “it’s critical to intervene early,” he told a session.
But Yu’s group and others are now extending the customized ASO approach, known as “n of 1” because the drug is designed for just one or a few patients. A foundation has formed to provide the bespoke RNAs for free. The U.S. Food and Drug Administration (FDA) is developing guidance for testing, manufacturing, and monitoring the outcomes of the personalized treatments. And at the ASHG meeting, Yu balanced Mila’s outcome with a more hopeful tale of another young girl who was given a custom ASO and has seen her disease stabilize for now.
Developing a treatment for a genetic disease is often a multiyear quest. But after sequencing Mila’s genome, Yu’s team realized she had an extra stretch of DNA in a gene called CLN7 that disrupted the messenger RNA, or protein-building instructions, made from the gene. Yu realized this could potentially be overcome by quickly synthesizing an ASO that would stick to the RNA during its processing into a mature mRNA, hiding the error so that Mila’s cells would make protein correctly.
Yu’s team raced to get milasen through toxicological testing and FDA approval under a compassionate use protocol for life-threatening conditions. Mila was already blind and could not walk without help when the drug was first injected into her spinal fluid in early 2018. Although it helped her—she had fewer seizures and regained some muscle strength—her condition eventually worsened. But her story led many more families to seek help from Yu, who estimates that 10% to 15% of people with inherited diseases have a genetic error similar to Mila’s that can be treated with an ASO customized to match the flaw.
Among them was Ipek Kuzu, born in March 2017 with ataxia-telangiectasia (A-T), a neurodegenerative condition caused by a defect in a DNA repair gene. Ipek began to receive spinal infusions of a tailored ASO in January 2020, when she only had mild symptoms, such as a speech delay. Nearly 2 years later, Ipek has had no worsening of her problems. However, A-T’s more severe symptoms don’t appear until about age 5. “It’s still too early to declare success,” Yu said at the meeting.
Ipek’s father, Mehmet Kuzu, is realistic: If Ipek doesn’t need a wheelchair until her late teens, instead of the usual age of 9 or 10, “it will be a very big difference,” he says. Other children might also benefit. Yu has come across four A-T children with the same mutation as Ipek. “We are a little bit guilty of a misnomer by calling these drugs individualized,” he said in his online talk.
Similarly, the biotech company Ionis Pharmaceuticals in 2019 rushed through regulatory steps to give 26-year-old Jaci Hermstad a custom ASO for her rare inherited early-onset form of amyotrophic lateral sclerosis (ALS). Seriously ill when treatment began, she died in May 2020. However, 10 other ALS patients with the same mutation have started on the ASO, jacifusen, and some have had signs of clinical improvement, says neurologist Neil Shneider of Columbia University, who works with the company.
Ionis launched a 64-patient clinical trial in April to test jacifusen compared with a placebo. Extending a custom ASO’s use to other patients helps defray the staggering cost of safety testing the molecule in animals—typically more than $1 million.
Early treatment with a custom ASO may be less crucial for nonprogressive genetic disorders. Rush University Medical Center neurologist Elizabeth Berry-Kravis leads an ASO trial for Angelman syndrome, in which children develop intellectual disabilities. The drug binds to the mRNA for a protein that turns off the paternal copy of gene called UBE3A so the gene is activated and makes up for problems with the mother’s version.
In all five participants, her team saw striking changes, including acquiring new words and sleeping better, she said at the ASHG meeting. Although younger children improved more, teens made gains, too. “The neurons are all still there, they’re just not wired right,” Berry-Kravis said.
The trial was halted 1 year ago because inflammation around the injection site caused temporary leg weakness in patients, but it has restarted outside the United States with a lower drug dose. Such side effects are one potential obstacle with ASOs delivered to the spinal cord, retired Ionis CEO Stanley Crooke cautioned at the ASHG meeting.
Still, in January 2020 he created the n-Lorem Foundation to accelerate tailored ASOs for “ultrarare” disease mutations—shared by no more than 30 people, too few to interest most drug companies. It is working with more than 35 families and hopes to treat the first patient, a boy with a developmental disorder caused by an uncommon mutation, early next year.
Academic groups in several countries are also working on customized ASOs. Yu cautions that as researchers move forward with more n-of-1 ASO treatments, they must “avoid raising expectations too quickly.” But even if the outcome is uncertain, the risk is worth taking, Mehmet Kuzu says. With his daughter Ipek’s disease, “If nothing is done, we know what will happen.”