Tofersen

Jin J, et al. Trends in Pharmacological Sciences, 2023, 44(12), 1043-1044.

Tofersen is an antisense oligonucleotide (ASO) designed for the treatment of amyotrophic lateral sclerosis (ALS) associated with superoxide dismutase 1 (SOD1) mutations. Approximately 2% of ALS cases are linked to SOD1 gene mutations, resulting in dysfunctional protein production that contributes to motor neuron degeneration.
Tofersen is a 20-base residue RNA-DNA-RNA (5-10-5) gapmer oligonucleotide that selectively targets and degrades mutated SOD1 mRNA. Upon intrathecal administration, the molecule enters motor neurons and astrocytes via endocytosis, with some escaping the endosomal pathway into the cytoplasm. There, tofersen binds to the mutant mRNA, forming a DNA:RNA heteroduplex. This structure is recognized by RNase H, which enzymatically cleaves the mRNA, halting the production of the aberrant SOD1 protein. This reduction in dysfunctional protein synthesis mitigates ALS progression in affected patients.
Tofersen is indicated for adults with confirmed SOD1 mutations. The recommended dosing regimen involves three loading doses (100 mg each) at 14-day intervals, followed by a maintenance dose every 28 days. Administration is via intrathecal injection, ensuring delivery to the central nervous system.