Experimental treatment shows promise in patient with rare genetic form of ALS

A novel treatment for amyotrophic lateral sclerosis (ALS) caused by mutations in a specific gene called CHCHD10 showed promise for slowing disease progression in a clinical trial that tested the therapy in a single individual, as reported in a new study.

“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. It speaks to the power of science and how far genetically targeted treatments have come,” Björn Oskarsson, MD, senior author of the study at the Mayo Clinic, said in a clinic news story.

The study, “N-of-1 investigational study of a novel antisense oligonucleotide drug in CHCHD10-related ALS shows early signs of efficacy,” was published in Med.

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Therapy designed to shut down the CHCHD10 gene

ALS is a progressive disorder in which motor neurons, the nerve cells that control movement, gradually sicken and die. The causes of ALS aren’t fully understood, but genetic mutations are known to underlie at least some cases.

Mutations in the CHCHD10 gene are a rare genetic cause of ALS. These mutations lead to the production of an abnormal CHCHD10 protein, which is thought to drive motor neuron damage.

In this study, genetic testing identified an individual with ALS caused by a CHCHD10 gene mutation. To create a treatment targeting the mutation, researchers at Mayo collaborated with the n-Lorem Foundation, a nonprofit that develops medicines based on antisense oligonucleotides.

Antisense oligonucleotides (ASOs) are short, synthetic pieces of genetic material that can be designed to shut down the activity of specific genes. In this case, researchers created ASOs designed to shut down the CHCHD10 gene, with the goal of reducing production of the mutated CHCHD10 protein to slow disease progression.

After screening more than 320 candidates in lab models, a single experimental therapy dubbed nL-CHCHD-001 was selected for testing in an N-of-1 clinical trial (NCT06392126), which means a clinical study with only one participant.

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Levels of nerve damage marker decreased by about 50%

Over the course of one year, the patient received six injections of this experimental therapy administered intrathecally, or by injection into the spinal canal. Safety findings were positive, as the patient reported mild-to-moderate headache and fatigue following the injections. No serious side effects occurred.

Prior to starting treatment, the patient had higher-than-normal levels of neurofilament light chain (NfL), a marker of nerve damage. Over the course of a year of treatment, NfL levels decreased by about 50% — to the point that levels of this biomarker were within normal ranges at the latest follow-up.

“The quick response in neurofilament light was very encouraging,” Oskarsson said.

ALS is a progressive disease, meaning symptoms tend to worsen as time goes on. However, in direct contrast to this typical pattern, standardized assessments suggested that the patient’s symptoms slightly improved over a year of treatment.

As we learn how to scale these approaches, the impact could reach far beyond ultrarare disease..

Specifically, scores on the ALS Functional Rating Scale-Revised, which measures the ability to perform daily functions, improved from 33 to 36, while vital capacity — a standard assessment of breathing ability — improved from from 48% to 55%. Measures of cognition and life quality were stable over the course of the yearlong study.

The researchers stressed that this study was limited to a single patient, making it impossible to draw broad conclusions. Still, they said the result “demonstrates the feasibility of developing individualized ASO therapy for CHCHD10-related ALS and provides preliminary evidence of biomarker and clinical benefit.” The team called for further testing of this approach.

“Cases like this are how we get started,” said Margot Cousin, PhD, director of the N-of-1 Therapeutics Program at Mayo 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.”