Researchers report early results from therapy designed for a single patient with a rare genetic form of ALS

Mayo Clinic researchers have reported promising early results from an experimental therapy targeting a rare genetic form of amyotrophic lateral sclerosis (ALS). The single-patient study, published in Med, suggests that precision medicine - using a disease's genetic cause to inform highly targeted treatments - could offer hope for patients with rare conditions that often have limited treatment options.

Dr. Björn Oskarsson, a neurologist at Mayo Clinic and senior author of the study, expressed enthusiasm about the potential of genetically targeted therapies, stating that it reflects the "power of science" in developing treatments for ALS. The research builds upon decades of ALS genetics work at Mayo Clinic, beginning with the discovery of a key mutation in the C9orf72 gene in 2011.

In this study, researchers identified a mutation in the CHCHD10 gene, which was shown to produce a harmful protein linked to abnormal changes in TDP-43, another protein closely associated with ALS. To develop the therapy, Mayo Clinic collaborated with the nonprofit n-Lorem Foundation, which specializes in creating medicines based on antisense oligonucleotides (ASOs).

ASOs are short synthetic strands of genetic material designed to bind to RNA and reduce the production of disease-causing proteins. The foundation tested over 320 ASOs targeting CHCHD10 before selecting a lead candidate based on its specificity and early safety profile. The experimental therapy, delivered through injections into the fluid surrounding the spinal cord, consisted of six doses.

Preliminary findings indicate that the treatment was well-tolerated, with blood levels of neurofilament light - a biomarker for nerve-cell injury - declining by up to 50%. Additionally, measures of breathing, cognition, and physical function remained stable or showed modest improvement. While the study's small sample size and short duration preclude definitive conclusions about the therapy's efficacy or long-term safety, researchers see these early observations as encouraging.

They also provide a unique opportunity to study the molecular effects of the therapy, such as changes in TDP-43 levels, mitochondrial function, and gene activity. The experimental nature of the treatment means it is not currently considered standard clinical care. However, Mayo Clinic researchers estimate that around 50% of ALS cases are genetic, though only a subset of these may be suitable for an ASO-based approach.

Some genetic forms may require alternative strategies, such as gene editing. The study is part of Mayo Clinic's broader N-of-1 Therapeutics Program, which aims to develop standardized frameworks for conducting individualized genetic therapies. By learning from these cases, researchers hope to establish safety benchmarks, refine treatment platforms, and identify which disease mechanisms are most responsive to targeted therapies.

The insights gained from studying ultrarare diseases could potentially inform new approaches for more common conditions, highlighting the broader impact of this research.