Gelsolin (GSN) mRNA (GSN)

Gelsolin (GSN) is a calcium-regulated protein responsible for severing, capping, and nucleating actin filaments, playing a critical role in cytoskeletal remodeling and cell motility [1, 4]. The GSN mRNA is a therapeutic target for Hereditary Gelsolin Amyloidosis (HGA), a condition where mutations in the GSN gene (notably D187Y/N) result in a protein that is susceptible to aberrant proteolysis, forming toxic amyloid fibrils [3]. These fibrils accumulate in various tissues, leading to a triad of symptoms including corneal lattice dystrophy, cranial neuropathy, and cutis laxa [3, 4]. Current therapeutic development focuses on using antisense oligonucleotides (ASOs) to target GSN mRNA, inducing its degradation to lower the levels of the mutant, amyloidogenic protein [2, 3]. This approach aims to halt the progression of amyloid deposition and the associated systemic organ damage [2]. By reducing the expression of the GSN gene at the transcript level, ASOs provide a precision medicine approach to treating the underlying cause of this rare genetic disorder [2, 3]. While gelsolin is also involved in apoptosis and inflammation, the reduction of its mutant form is hypothesized to outweigh the potential risks of lowering total gelsolin levels [1, 3].

Other names

GSNAGELADFBrevinActin-depolymerizing factor

Antisense oligonucleotide-mediated RNase H-dependent degradation of GSN mRNA to reduce the production of amyloidogenic gelsolin fragments.