麻豆AV

Abstract:

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Synthetic small interfering RNAs (siRNAs) are potent inhibitors of gene expression. These molecules are perfect examples of biomimetic chemistry as synthetic siRNAs act through the natural RNA interference (RNAi) pathway. To deliver therapeutic siRNAs into human liver, we developed approaches that include chemical modification of the siRNAs and either lipid nanoparticle (LNP) formulation or multivalent N-acetylgalactosamine (GalNAc) conjugation, making possible intravenous and subcutaneous administration, respectively. The design of chemical modifications of siRNAs to enable favorable Argonaute2 (Ago2) recognition as well as both delivery strategies rely on biomimetics. The LNP approach is based on the endogenous Apo-E ligand /LDL receptor process. Using these strategies five approved RNAi therapeutics have emerged from Alnylam. We have also used lipid conjugates for CNS delivery of therapeutic siRNAs.听

This presentation will cover the molecular basis of RNA therapeutics including the chemical modifications and motifs used in each RNA strand to ensure uptake into cells of the targeted tissue, Ago2 recognition, silencing efficiency, metabolic stability, and safety.

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Bio:

Dr. Muthiah (Mano) Manoharan serves as the Senior Vice President of Drug Innovation, a Scientific Advisory Board Member, and a Distinguished Research Scientist at Alnylam Pharmaceuticals, Cambridge, Massachusetts. In 2003, he was the founding chemist hired at Alnylam as the Head of the Drug Discovery. He and his team pioneered the discovery and development of numerous chemical modifications, GalNAc conjugation chemistry, lipid conjugates (the first in vivo demonstration of RNAi in 2004) and Lipid Nanoparticles (LNP) delivery platform that make RNA interference-based human therapeutics possible. This work led to the approval of five RNAi therapeutics: ONPATTRO庐 (patisiran, 2018), GIVLAARI庐 (givosiran, 2019), OXLUMO庐 (lumasiran, 2020), LEQVIO庐 (inclisiran, 2020, 2021) and AMVUTTRO庐 (vutrisiran, 2022).

Dr. Manoharan has had a distinguished career as a world-leading chemist in the field of oligonucleotide therapeutics. Prior to joining Alnylam, he worked at Isis (Ionis) Pharmaceuticals from 1990-2003 in the field of antisense oligonucleotides. He is an author of more than 250 publications (nearly 65,300 Google Scholar citations with an h-index of 116 and an i10-index of 436) and over 500 abstracts, as well as an inventor of over 290 issued U.S. patents.

Dr. Manoharan is the winner of the Lifetime Achievement Award of the Oligonucleotide Therapeutics Society (OTS, 2019), the M. L. Wolfrom Award (2007), D. Horton Industrial Carbohydrate Chemistry Award (2021) from the Carbohydrate Chemistry Division of the American Chemical Society, the Chemical Research Society of India (CRSI) 2022 Medal by the and the National Chemical Laboratory (NCL, Pune, India)-K. N. Ganesh award in 2023 . He was elected as a Fellow of the American Chemical Society in 2022. He has been honored with the Professor Ronald Breslow Biomimetic Chemistry National award by the American Chemistry for the year 2024.

Dr. Manoharan was born in Madurai, Tamil Nadu, India and received his B.Sc. and M.Sc. degrees in chemistry at the American College, Madurai, India. He earned his Ph.D. in chemistry at the University of North Carolina, Chapel Hill, (Professor Ernest L. Eliel) and learned the field of oligonucleotides at Yale University and University of Maryland as a post-doctoral research associate (Professor John A. Gerlt).

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