JACKSONVILLE, Fla. — Mayo Clinic researchers report encouraging early results from an experimental therapy targeting the genetic cause of a rare form of amyotrophic lateral sclerosis, or ALS. The study is published in Med.
The single-patient study points to a broader possibility in precision medicine — using the genetic cause of a disease as a framework for testing highly targeted therapies, particularly for patients with rare conditions that have few treatment options.
“I didn’t think I would see this kind of research in my lifetime — identifying a disease-causing mutation, developing an experimental therapy and delivering it to a patient,” says Björn Oskarsson, M.D., a Mayo Clinic neurologist and senior author of the study. “It speaks to the power of science and how far genetically targeted treatments have come.”
Targeting genetic ALS
That work builds on a long history of ALS genetics research at Mayo Clinic. In 2011, then-Mayo Clinic neurogeneticist Rosa Rademakers, Ph.D., and colleagues helped discover a mutation in the C9orf72 gene, now recognized as the most common inherited genetic cause of ALS. Dr. Rademakers received the 2026 Breakthrough Prize in Life Sciences for her role in the discovery. Mayo researchers also developed early models that helped scientists investigate how the mutation contributes to ALS.
Since joining Mayo, Dr. Oskarsson has helped translate advances in ALS genetics into treatment research, contributing to the first approved treatment of genetic ALS.
ALS progressively damages motor neurons, the nerve cells that control voluntary movement. In this study, genetic testing identified a mutation in CHCHD10, a gene associated with a rare form of ALS. The mutation appears to make the CHCHD10 protein harmful to nerve cells and is linked to abnormal changes in TDP-43, a protein closely associated with ALS.
Mayo researchers collaborated with the nonprofit n-Lorem Foundation, which develops medicines based on antisense oligonucleotides, or ASOs, for people with ultrarare genetic diseases. ASOs are short synthetic strands of genetic material designed to bind to RNA and reduce production of a protein that contributes to disease. The foundation developed and evaluated more than 320 ASOs targeting CHCHD10 before selecting a lead candidate based on specificity and early safety testing.
Early signs of treatment response
The study reports on the patient’s first six doses of the experimental ASO, delivered through injections into the fluid surrounding the spinal cord. Treatment was well tolerated, and levels of neurofilament light — a blood biomarker of nerve-cell injury — declined by as much as 50%. Measures of breathing, cognition and physical function remained stable or showed modest improvement.
“The quick response in neurofilament light was very encouraging,” Dr. Oskarsson says. In a progressive disease such as ALS, he adds, stabilization can be a meaningful observation.
The study also gives researchers a chance to look more closely at what is happening inside cells during the therapy. Using samples collected before and during the delivery of the ASOs, the team is studying changes in TDP-43 as well as mitochondrial function and gene activity. The goal is to understand how suppressing CHCHD10 may affect the disease process at a molecular level.
The therapy remains experimental research and is not standard clinical care. Dr. Oskarsson estimates that about 50% of ALS is genetic, but he notes that only a subset of those cases are currently suited to an antisense approach. Some genetic forms may require other strategies, including gene editing.
A framework for precision
The study is part of a broader effort through Mayo Clinic’s N-of-1 Therapeutics Program to learn which elements of drug development, clinical evaluation and monitoring can be applied across individualized genetic therapies.
“Cases like this are how we get started,” says Margot Cousin, Ph.D., director of the N-of-1 Therapeutics Program and lead author of the study. “They help us build the scientific, clinical, translational and regulatory framework to do this rigorously and equitably. As we learn how to scale these approaches, the impact could reach far beyond ultrarare disease.”
Research in ultrarare diseases can help establish safety benchmarks, refine genetic-treatment platforms and clarify which disease mechanisms are most amenable to targeted therapy. Those lessons could ultimately inform new approaches to more common diseases.
For a complete list of authors, disclosures and funding, review the study.
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