Results from a case series of patients with amyotrophic lateral sclerosis (ALS) suggest that an experimental antisense oligonucleotide (ASO) that silences fused in sarcoma (FUS) gene variants could potentially prevent or delay onset and progression of the disease.
Although FUS gene mutations are responsible for only 1% to 2% of all ALS cases, FUS-ALS is one of the most aggressive forms of ALS that can begin in adolescents and young adults. In patients with these mutations, toxic FUS proteins accumulate in the motor neurons that control the patient’s muscles, eventually killing the neurons.
“When testing new drugs for ALS, we do not expect to see clinical improvement,” says Neil Shneider, M.D., Ph.D., a neurologist and director of the Eleanor and Lou Gehrig ALS Center at NewYork-Presbyterian and Columbia and lead author of the series, which was published in The Lancet. “We saw unprecedented functional recovery in one young patient, and overall, the results of this study were encouraging. It’s surprising and deeply motivating not only for us and the ALS research community, but also for the community of ALS patients.” The drug is now completing phase 3 clinical trial.
Illustration of the degeneration of motor neurons. Ulefnersen silences the FUS gene that eventually kills neurons, helping to slow progression of ALS.
The First Use of Ulefnersen
The drug, called ulefnersen, was first administered to a patient in 2019, when Dr. Shneider received special permission through the Food and Drug Administration’s expanded access program to administer it to a patient named Jaci Hermstad, whose identical twin had died from FUS-ALS. Ulefnersen was designed to silence the FUS gene and reduce production of toxic and normal FUS proteins. Although Jaci died a year later due to her advanced disease, the medication slowed her functional decline, and Dr. Shneider continued to test the therapy — originally named jacifusen, after her — in a mouse model.
“Because we found that mature neurons tolerate a reduction of normal FUS protein, our studies provided the rationale for treating FUS-ALS patients with this drug,” Dr. Shneider says. Since then, at least 25 patients have been treated with ulefnersen around the world in expanded access programs, including the 12 patients described in the case series. The results showed that after six months of treatment, patients experienced up to an 83% decrease in neurofilament light, a cerebrospinal fluid biomarker of nerve damage. Additionally, tissue samples from four participants showed reduced FUS protein levels and a decrease in the burden of FUS pathology.
Two participants showed a remarkable response. One young woman, who has received injections of ulefnersen since late 2020, recovered the ability to walk unaided and to breathe without the use of a ventilator. She has lived longer with this disease than any other known patient with this juvenile-onset form of FUS-ALS, says Dr. Shneider.
These responses show that if we intervene early enough and go after the right target at the right time, it's possible to not only slow disease progression, but actually reverse some of the functional losses.
— Dr. Neil Shneider
Another patient, a man in his mid-30s whose mother and sisters died from ALS, was asymptomatic when he began treatment, but his electromyography results indicated that symptoms would likely emerge soon. In three years of continuous treatment, he has yet to develop symptoms of FUS-ALS, and the abnormal electrical activity in his muscles has improved.
“These responses show that if we intervene early enough and go after the right target at the right time in the course of disease, it's possible to not only slow disease progression, but actually reverse some of the functional losses,” says Dr. Shneider. “It’s also a wonderful example of precision medicine and therapeutic development based on science and an understanding of the biology of disease.”
Although most of the other symptomatic patients in the series did not survive their aggressive disease, Shneider says the progression of their disease likely slowed, prolonging their life expectancy. The case series also showed that ulefnersen is safe and well-tolerated, with no serious adverse events.
The therapy is now being studied in a global, industry-sponsored clinical trial led by Dr. Shneider. “We are eagerly awaiting those results, which we hope will lead to the approval of ulefnersen,” he says.
Expanding ASO Research
In 2022, Dr. Shneider launched the Silence ALS program, a joint effort between Columbia and the n-Lorem Foundation, to continue to develop antisense oligonucleotides for various ultra-rare forms of ALS. The program has already successfully used gene-silencing technology to develop an ASO treatment for mutations in the TARDBP gene, which has now been tried in three patients, and CHCHD10, involving 13 patients. Additional ALS patients with mutations in these genes are expected to be treated in the coming months.
In 2024, the program was awarded $15 million from the Ultra-Rare Gene-based Therapy Network (URGenT) of the National Institute for Neurological Disorders and Stroke to develop additional ASO treatments. The grant will fund the development of at least nine ASOs over the three-year award period.
Altogether, mutations in FUS, TARDBP, CHCHD10, and other genes are responsible for about one in eight ALS cases. Says Dr. Shneider, “ASOs could not only improve treatment for a substantial fraction of ALS patients who have genetic mutations, but also inform our understanding of, and therapeutic approach to, more common forms of ALS that have no known genetic cause.”
A version of this article originally appeared in Columbia’s newsroom.
