Typically, the goal of ALS treatments is to slow the disease or halt progression. But new data from the antisense oligonucleotide (ASO) jacifusen for FUS-ALS show that two patients went beyond the expected, and showed improvements.
“When testing new drugs for ALS, we do not expect to see clinical improvement,” said Neil Shneider, MD, PhD, director of the Eleanor and Lou Gehrig ALS Center and associate professor of motor neuron disorders at Columbia University College of Physicians and Surgeons. “What we’ve seen in one patient is really unprecedented functional recovery. It’s surprising and deeply motivating for us, the ALS research community, but also the community of ALS patients.”
Data from 12 patients—all treated with the novel therapy for a rare form of ALS caused by a genetic mutation in a gene called FUS—were presented in a case series. This work is published in The Lancet in the paper, “Antisense oligonucleotide jacifusen for FUS-ALS: an investigator-initiated, multicenter, open-label case series.”
Pathogenic variants of fused in sarcoma (FUS) cause amyotrophic lateral sclerosis (FUS-ALS), with evidence of gain of function. Jacifusen is an antisense oligonucleotide targeting FUS pre-mRNA. The ASO has previously been shown to delay neurodegeneration in a mouse model.
Though these gene mutations are responsible for only 1% to 2% of ALS cases, they cause some of the most aggressive forms of ALS that 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.
Two of the patients showed a remarkable response to the experimental therapy, ulefnersen (previously known as jacifusen), which was developed by Shneider in collaboration with Ionis Pharmaceuticals.
One young woman, who has received injections of the therapy since late 2020, recovered the ability to walk unaided and to breathe without the use of a ventilator, both previously lost to ALS. She has lived longer with this disease than any other known patient with this juvenile-onset form of FUS-ALS.
The second patient, a man in his mid-30s, was asymptomatic when he began treatment, but tests of electrical activity in his muscles indicated that symptoms would likely emerge soon. In three years of continuous treatment with the experimental drug, the man has yet to develop any symptoms of FUS-ALS and the abnormal electrical activity in his muscles has improved.
Overall, after six months of treatment, patients in the series experienced up to an 83% decrease in a protein called neurofilament light, a biomarker of nerve damage.
“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,” Shneider said. “It’s also a wonderful example of precision medicine and therapeutic development based on science and an understanding of the biology of disease.”
Though most of the other symptomatic patients in the series did not survive their aggressive disease, Shneider said, “several apparently benefited from the treatment. The progression of their disease slowed, and they lived a longer life as a consequence.”
After seeing results from the first of these patients, Ionis Pharmaceuticals committed to sponsoring a global clinical trial of the drug, led by Shneider, which is now in progress. “Now we are eagerly awaiting those results, which we hope will lead to the approval of ulefnersen,” Shneider said.
The development of ulefnersen began as an effort to help a single patient. Shneider first tested the therapy six years ago in a patient from Iowa, Jaci Hermstad, whose identical twin had died from the disease years earlier. He had good reason to believe the drug might work. Just a few years earlier, his research in mice revealed that the FUS mutations cause cells to make proteins that are toxic to motor neurons. The results suggested that reducing levels of toxic FUS proteins could prevent or delay onset and progression of ALS.
Ulefnersen was designed to silence the FUS gene and reduce production of toxic and normal FUS proteins. “Because we also found that mature neurons tolerate a reduction of normal FUS protein, our studies provided the rationale for treating FUS-ALS patients with this drug,” Shneider said.
In 2019, Shneider requested permission from the FDA to administer ulefnersen to Jaci. Since then, at least 25 patients have been treated with ulefnersen (originally named jacifusen for Jaci Hermstad) around the world in expanded access programs.
