NEW YORK (GenomeWeb) – Researchers from Mount Sinai School of Medicine, along with collaborators from Alnylam Pharmaceuticals, reported this week new animal data showing that RNAi can be used to prevent and treat the neurovisceral attacks that characterize acute intermittent porphyria (AIP).
The findings, which provide additional proof of concept for Alnylam's preclinical AIP treatment ALN-AS1, are based on experiments using siRNAs formulated in lipid nanoparticles and show that such agents are effective at doses as low as 1 mg/kg.
Alnylam is basing ALN-AS1 on its GalNAc conjugate subcutaneous delivery technology. In previous preclinical studies, the drug was able to achieve the desired level of target gene knockdown at a dose of 2.5 mg/kg in rats and at 1.25 mg/kg non-human primates.
The drug is designed to silence ALAS-1, an enzyme upstream of the porphobilinogen deaminase gene, which is defective in the disease.
The new preclinical data, which appeared in Proceedings of the National Academy of Sciences, show that siRNAs targeting ALAS-1 completely protected mouse models of AIP from phenobarbital-induced up-regulation of hepatic ALAS-1 mRNA and protein. Treatment also prevented the abnormal accumulation of toxic heme intermediates — specifically aminolevulinic acid (ALA) and porphobilinogen (PBG) — that mediate AIP symptoms and pathology.
"This protective effect was dose responsive and durable, with a single dose administration resulting in a protective effect that lasted for at least two weeks," Alnylam said.
Meanwhile, in a treatment model of AIP, a single dose of ALAS-1-targeting siRNAs rapidly reduced the high levels of plasma ALA and PBG that were elevated during a phenobarbital-induced acute attack, the company added.
Treatment was also associated with a significant improvement in motor performance as compared with animals treated with a control siRNA, suggesting that ALN-AS1 can protect against symptoms of neuromotor impairment associated with AIP attacks.