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When Columbia neurologist and scientist Neil Shneider speaks to his ALS sufferers who volunteer for experimental therapies, he is unwaveringly trustworthy. “Patients always ask me, ‘What can I hope to get out of this?”‘ Shneider says. “And I always say, in most clinical trials, our hope is that we can slow the disease or maybe even halt progression.”
So it was a giant shock when a number of the sufferers handled with an experimental drug—a remedy that emerged from Shneider’s analysis efforts—confirmed enhancements.
“When testing new drugs for ALS, we do not expect to see clinical improvement,” Shneider says. “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.”
Outstanding success tales
Information from 12 sufferers—all handled with the novel remedy for a uncommon type of ALS brought on by a genetic mutation in a gene referred to as FUS—have been offered in a case sequence revealed by Shneider on-line in The Lancet.
Although these gene mutations are chargeable for only one–2% of ALS instances, they trigger a number of the most aggressive types of ALS that start in adolescents and younger adults. In sufferers with these mutations, poisonous FUS proteins accumulate within the motor neurons that management the affected person’s muscle groups, ultimately killing the neurons.
Two of the sufferers within the revealed case sequence confirmed a outstanding response to the experimental remedy, ulefnersen (beforehand generally known as jacifusen), developed by Shneider in collaboration with Ionis Prescribed drugs.
One younger lady, who has obtained injections of the remedy since late 2020, recovered the flexibility to stroll unaided and to breathe with out the usage of a ventilator, each beforehand misplaced to ALS. She has lived longer with this illness than another recognized affected person with this juvenile-onset type of FUS ALS.
The second affected person, a person in his mid-30s, was asymptomatic when he started therapy, however assessments {of electrical} exercise in his muscle groups indicated that signs would seemingly emerge quickly. In three years of steady therapy with the experimental drug, the person has but to develop any signs of FUS-ALS and the irregular electrical exercise in his muscle groups has improved.
General, after six months of therapy, sufferers within the sequence skilled as much as an 83% lower in a protein referred to as neurofilament mild, a biomarker of nerve injury.
“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 says. “It’s also a wonderful example of precision medicine and therapeutic development based on science and an understanding of the biology of disease.”
Although a lot of the different symptomatic sufferers within the sequence didn’t survive their aggressive illness, Shneider says “several apparently benefited from the treatment. The progression of their disease slowed, and they lived a longer life as a consequence.”
The case sequence additionally confirmed that the drug is secure and properly tolerated, with no critical hostile occasions associated to the drug.
“Now we are eagerly awaiting those results, which we hope will lead to the approval of ulefnersen,” Shneider stated.
The story behind ulefnersen
The event of ulefnersen started as an effort to assist a single affected person and has grown right into a full-scale scientific trial that might assist many sufferers with this aggressive type of ALS.
Shneider first examined the remedy six years in the past in a affected person from Iowa, Jaci Hermstad, whose similar twin had died from the illness years earlier. Shneider labored with Ionis Prescribed drugs to develop a drug, by no means examined in folks, which may sluggish the development of Jaci’s signs.
He had good purpose to imagine the drug may work. Only a few years earlier, his analysis in mice revealed that the FUS mutations trigger cells to make proteins which can be poisonous to motor neurons. The outcomes urged that lowering ranges of poisonous FUS proteins might stop or delay onset and development of ALS.
Shneider believed the drug could be a robust option to scale back FUS proteins. The drug belongs to an rising and extremely promising class that makes use of brief items of DNA, referred to as antisense oligonucleotides, or ASOs, to silence particular genes and halt the manufacturing of the proteins they encode.
Ulefnersen was designed to silence the FUS gene and scale back the manufacturing of poisonous and regular 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 says.
In 2019, Shneider requested permission from the FDA to manage ulefnersen to Jaci by its expanded entry program, generally referred to as “compassionate use.”
Since then, no less than 25 sufferers have been handled with ulefnersen (initially named jacifusen for Jaci Hermstad) world wide in expanded entry applications, together with the dozen sufferers described in The Lancet article.
Extra info:
Antisense oligonucleotide jacifusen for FUS-ALS: an investigator-initiated, multicentre, open-label case sequence, The Lancet (2025). DOI: 10.1016/S0140-6736(25)00513-6
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Columbia College Irving Medical Heart
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Experimental drug could profit some sufferers with uncommon type of ALS (2025, Might 22)
retrieved 22 Might 2025
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