Synthesis and Biological Activity Assessment of Different Diastereomers in siRNA Drug LEQVIO (Inclisiran) (U01) Clinical Trial Not Allowed
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The research aims to systematically analyze the diastereomeric composition of LEQVIO (Inclisiran), an FDA-approved GalNAc-conjugated siRNA therapeutic, by synthesizing each diastereomer in stereochemically pure form and evaluating their individual biological and pharmacological activities. Studies will assess the ability of each pure diastereomer to inhibit PCSK9 using in vitro assays and a transgenic mouse model, determining their relative contributions to the drug’s overall efficacy. Advanced analytical methods will be developed to identify and characterize the stereochemical structure of each diastereomer within the commercial formulation, enabling precise quantification and quality assessment. The findings will clarify how stereochemical variation influences therapeutic activity, providing critical insights for evaluating the sameness of future generic siRNA drugs and improving quality control standards for oligonucleotide-based therapeutics. The tools and methodologies established through this work are designed to be broadly applicable to other GalNAc-conjugated siRNAs and siRNA platforms in general.
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The purpose of this research is to systematically evaluate the diastereomeric composition of LEQVIO (Inclisiran), an FDA-approved, N-acetyl galactosamine (GalNAc)-conjugated siRNA drug, and to understand the biological/pharmacological activity of each diastereomer in LEQVIO through stereo chemically controlled synthesis and biological activity assessment using in vitro and animal models. The proposed studies will focus on 1) synthesis of each diastereomer of LEQVIO (Inclisiran) in stereo chemically pure form; 2) assessment of the biological activity of each stereo chemically pure diastereomer in inhibiting PCSK9 activity using in vitro assays and in a transgenic mouse model; 3) development of analytical methods to identify and characterize the stereochemical structure of each diastereomer in LEQVIO; and 4) assessment of the individual contribution of each diastereomer to the overall pharmacological activity of LEQVIO. Tools developed in this research can also be applied to other similar GalNAc-conjugated siRNAs specifically, and other siRNAs in general. Knowledge gained from this research will also contribute to the sameness evaluation of generic siRNAs, and to the quality control of oligonucleotide drugs.
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