8:01AM Alnylam Pharma presents new pre-clinical data on RNAi Therapeutics for the treatment of Alpha-1 Antitrypsin (AAT) Deficiency; single intravenous dose of the drug resulted in 90% knockdown of liver mRNA and a greater than 80% decrease in serum AAT at 48 hours post-dose (ALNY) 16.94 : ALN-AAT is a new RNAi therapeutic program for the treatment of liver disease associated with AAT deficiency. New data presented at the Liver Meeting are based on an AAT-targeting siRNA formulated in a lipid nanoparticle (LNP). The AAT siRNA was administered at doses ranging from 0.03 to 1.0 mg/kg in mice overexpressing a human Z-AAT transgene, resulting in robust, dose-dependent silencing of the target mRNA and protein. Specifically, a single intravenous dose of the drug resulted in 90% knockdown of liver mRNA and a greater than 80% decrease in serum AAT at 48 hours post-dose. Furthermore, a 90% reduction in soluble protein monomers in the liver was observed at 1.0 mg/kg, with an 80% reduction seen at 0.3 mg/kg. In addition, in long-term dosing studies, in which transgenic mice overexpressing Z-AAT were dosed every other week for 12 weeks at 0.3 mg/kg, ALN-AAT resulted in a 45% reduction of pathogenic protein polymers and a significant decrease in the size and number of AAT globules in hepatocytes. Long-term dosing also significantly decreased hepatocyte proliferation and liver collagen levels, known markers of liver dysfunction and fibrosis, respectively. Further, ALN-AAT administration resulted in marked improvements in hepatocyte cellular morphology as assessed by electron microscopy. Finally, 98% suppression of liver mRNA and serum protein was observed 48 hours after a single dose of the drug in transgenic mice that had fibrotic livers, illustrating key pre-clinical proof of concept for RNAi-mediated treatment in diseased livers. Alnylam has also identified a GalNAc-siRNA targeting AAT that enables subcutaneous dose administration for further development.
