Allele Selective and splice-switching FUS targeted antisense oligonucleotide therapeutic development for ALS

Rita Mejzini,¹,²,³ Loren Flynn,¹,²,³ Marvin Caruthers,⁶ Anthony Akkari,¹,²,³,⁴,⁵

¹Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Perth, Western Australia.
²Perron Institute for Neurological and Translational Science, Perth, Western Australia.
³Black Swan Pharmaceuticals, Perth, Western Australia. 4The University of Western Australia, Perth, Western Australia
⁵Duke University, North Carolina, USA. 6Department of Biochemistry, University of Colorado, Boulder, USA.

FUS is involved in important processess including gene regulation, DNA damage repair and in cellular responses to stress. Pathogenic FUS variants are associated with aggressive and early onset ALS. Antisense oligonucleotides (AOs) are nucleic acid analogues that are designed to bind to a target RNA and modulate gene expression through various mechanisms. A range of chemical modifications, including alternative nucleobase, sugar and linkage modifications are routinely used in AO design and have been essential to the success of AO based medicines. This work aims to improve on the AO therapeutic that is currently undergoing clinical trial in FUS-ALS patients by utilising different therapeutic strategies and chemistries.