Silence Therapeutics explores different options for fine tuning of GalNAc-conjugated siRNA design. Areas of special interest include siRNA modification patterns, end stabilisation, linker chemistry, and the number and location of GalNAc units. One in house discovery is that two single GalNAc units, positioned a distance apart on the sense strand, demonstrated increased activity and duration of action in wild type mice for a tool compound targeting TTR, compared to a “traditional” GalNAc triantennary design of the same siRNA sequence. At day 27 after single injection the novel design resulted in 85% reduction of target serum protein, compared to 36% reduction by equimolar amount of the control molecule. This design, as part of a molecule design toolbox, is being validated for novel siRNA GalNAc conjugates that may eventually be used as therapeutic options in liver-centric disease. We are also optimistic that the same design/synthesis principle will be useful when designing siRNA conjugates for extra-hepatic purposes.