Optimizing Drill Guide Positioning for Foveal Targeting in Arthroscopic One-Bone Tunnel Triangular Fibrocartilage Complex Repair: A Radiographic and Magnetic Resonance Imaging-Based Study.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition characterized by focal and then disseminated weakness, loss of motor function, and a median age of onset of 50–60 years. ALS patients typically survive 2–5 years after diagnosis, with respiratory muscle failure being the most common cause of death. Up to 90% of ALS cases are sporadic. The remaining cases are familial, typically transmitted as dominant traits; these arise from mutations in several genes, including (∼40% of familial cases) and superoxide dismutase (, 20%), followed by fused-in-sarcoma (, 5%) and transactive DNA-binding protein (, 5%). Mutations in and , respectively, account for ∼1% and 10% of sporadic ALS. SOD1 is an antioxidant enzyme that catalyzes the conversion of reactive oxygen species to oxygen and water. The pathophysiology of mutant SOD1 is complex. Many mutant SOD1 proteins show conformational instability and can be induced to aggregate, provoking multiple types of cellular dysfunction, many mediated by adverse oxidative activity. In transgenic ALS mouse models, knockdown of SOD1 delayed disease onset and preserved neuromuscular junction (NMJ) integrity. Thus, reducing SOD1 expression in the context of ALS is a promising treatment approach. In 2023, tofersen, a chemically stabilized antisense oligonucleotide (ASO) that reduces SOD1 mRNA and protein expression, became the first and only FDA (Federal Drug Administration, CDER, USA)- and EMA (European Medical Association, European Union)-approved drug specifically for SOD1 familial ALS. Tofersen is pan-SOD1 silencing, targeting both non-mutant and mutant SOD1 alleles. Although the clinical trial failed to reach its clinical endpoint (improvement in ALSFRS-R score), tofersen was ultimately approved after results during the open-label extension showed that disease progression was stabilized in patients who received earlier initiation of tofersen treatment versus those who received delayed treatment. Tofersen also reduced levels of the neuronal injury marker, neurofilament light chain (Nfl), suggesting attenuation of neuronal loss following SOD1 reduction. Although tofersen represents a profound advance in therapy for SOD1 ALS, tofersen’s clinical success is potentially limited by unfavorable pharmacokinetic and pharmacodynamic (PK/PD) properties of its GapmeR ASO design (modified RNA flanks with an unmodified DNA core) including limited on-target SOD1 lowering, frequent administration, and a high-dose regimen. A more robust treatment that can halt, prevent, or reverse SOD1-mediated familial ALS would be preferable for patients with this devastating condition.