Columbia University Irving Medical Center researchers have announced promising results for an experimental drug called ulefnersen in treating a rare, aggressive form of amyotrophic lateral sclerosis (ALS) that primarily affects adolescents and young adults.
The therapy targets FUS-ALS, caused by a genetic mutation in the FUS gene, which provides instructions for making a protein crucial in cellular processes. While FUS mutations account for only 1-2% of ALS cases, they lead to some of the most aggressive forms of the disease with early onset.
Unprecedented Functional Recovery
"When testing new drugs for ALS, we do not expect to see clinical improvement," said neurologist and scientist Dr. Neil Shneider, who developed the drug in collaboration with Ionis Pharmaceuticals. "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."
The findings, published in The Lancet, detail a small case series that began as an effort to help a single patient but expanded to include 12 individuals treated with ulefnersen.
Two patients demonstrated remarkable responses. A young woman who received ulefnersen injections since late 2020 regained the ability to walk unaided and breathe without ventilator support—functions previously lost to ALS progression. According to the medical center, she has survived longer with juvenile-onset FUS-ALS than any other known patient.
In another case, a man in his mid-thirties began treatment while still asymptomatic, though electrical activity tests in his muscles indicated imminent symptom development. After three years of treatment, he remains symptom-free, and the abnormal electrical activity in his muscles has improved.
Biomarker Evidence of Efficacy
The research team also documented an up to 83 percent decrease in neurofilament light—a biomarker of nerve damage—following six months of treatment with ulefnersen.
"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," explained 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."
Disease Context and Treatment Impact
ALS affects fewer than 30,000 people in the United States, with approximately 5,000 new diagnoses annually. The nervous system disease impacts nerve cells in the brain and spinal cord, causing progressive loss of muscle control. While most cases have no known cause, a small percentage are genetic. The disease currently has no cure and is eventually fatal.
While most symptomatic patients in the study did not survive their disease, Dr. Shneider noted that "several apparently benefited from the treatment. The progression of their disease slowed, and they lived a longer life as a consequence."
Safety Profile and Future Directions
The treatment demonstrated a favorable safety profile with no serious adverse events related to the drug. A global clinical trial is now underway, with at least 25 patients treated worldwide, including the 12 in Dr. Shneider's case studies.
The drug was first tested six years ago in an Iowa patient named Jaci Hermstad and was originally named for her.
"Now we are eagerly awaiting those results, which we hope will lead to the approval of ulefnersen," Dr. Shneider said.
This development represents a significant advance in precision medicine for ALS, particularly for young patients with the rare FUS mutation who previously had no effective treatment options.
