Gene-Targeted Therapies and Biomarkers Driving ALS Research Forward: Brian Lin, PhD

WATCH TIME: 3 minutes

“I think everyone in the field is really looking forward to seeing if some of the other genetically targeted therapies that are in the pipeline are going to be as successful as tofersen. We should really see those results coming up pretty soon.”

Recent progress in gene and RNA-targeted therapies has possibly reshaped the therapeutic landscape for amyotrophic lateral sclerosis (ALS), particularly for patients with known genetic mutations. The FDA’s accelerated approval of tofersen (Qalsody; Biogen) in 2023 for individuals with SOD1-mutated ALS represented a key milestone in this area.¹ Tofersen, an antisense oligonucleotide (ASOs), reduces production of toxic SOD1 protein, with real-world data suggesting it can slow disease progression and potentially improve motor function.² Beyond SOD1, emerging gene therapy approaches targeting other pathological proteins such as TDP-43, are in preclinical stages with trials anticipated in the coming years. These advances potentially point toward a future of genetically personalized care for ALS.³

As gene- and RNA-based therapies become more targeted, the need for accurate, responsive biomarkers to guide treatment decisions has maybe grown increasingly important. Biomarkers such as neurofilament light chain (NfL), measurable in both cerebrospinal fluid and plasma, have gained traction as reliable indicators of neuronal damage and disease progression in ALS.⁴ Elevated NfL levels are correlated with more rapid functional decline and shorter survival, supporting their use in both diagnosis and monitoring therapeutic efficacy.⁵ As these molecular tools evolve alongside therapeutic development, they can enable more precise stratification in clinical trials and potentially enhance the delivery of mechanism-based, personalized ALS care.

In a discussion on the current landscape of ALS research, Brian Lin, PhD, research portfolio director at the Muscular Dystrophy Association, sat down with NeurologyLive^® to highlight the significant progress in gene- and RNA-targeted therapies, particularly the impact of ASOs such as tofersen. He noted how real-world data are beginning to show disease stabilization and even functional improvement in some patients. Lin also underscored the importance of biomarkers such as NfL, neuroimaging, and wearable-derived metrics in both diagnosis and treatment response monitoring, potentially positioning the field toward more personalized and mechanism-based approaches.

REFERENCES
1. FDA approves treatment of amyotrophic lateral sclerosis associated with a mutation in the SOD1 gene. News release. FDA. April 25, 2023. Accessed May 4, 2025. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-treatment-amyotrophic-lateral-sclerosis-associated-mutation-sod1-gene
2. Ruffo P, Traynor BJ, Conforti FL. Advancements in genetic research and RNA therapy strategies for amyotrophic lateral sclerosis (ALS): current progress and future prospects. J Neurol. 2025;272(3):233. Published 2025 Feb 26. doi:10.1007/s00415-025-12975-8
3. Ke YD, van Hummel A, Au C, et al. Targeting 14-3-3θ-mediated TDP-43 pathology in amyotrophic lateral sclerosis and frontotemporal dementia mice. Neuron. 2024;112(8):1249-1264.e8. doi:10.1016/j.neuron.2024.01.022
4. Lv Y, Li H. Blood diagnostic and prognostic biomarkers in amyotrophic lateral sclerosis. Neural Regen Res. 2025;20(9):2556-2570. doi:10.4103/NRR.NRR-D-24-00286
5. Sturmey E, Malaspina A. Blood biomarkers in ALS: challenges, applications and novel frontiers. Acta Neurol Scand. 2022;146(4):375-388. doi:10.1111/ane.13698

Editor’s Note: Timothy Miller, MD, PhD, is the codirector at the MDA/ALS Care Center at Washington University in St. Louis.