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Dr Muthiah (Mano) Manoharan is the Senior Vice President of Drug Innovation, a Scientific Advisory Board Member, and a Distinguished Research Scientist at Alnylam Pharmaceuticals, Cambridge, Massachusetts. He joined Alnylam as the company鈥檚 first chemist in 2003. Under his leadership, the Alnylam team developed multiple RNA chemical modifications, including the lipid conjugates that led to the first in vivo demonstration of RNA interference (RNAi) in 2004. Dr. Manoharan was instrumental in development of the lipid nanoparticle delivery platform used for the first clinically approved RNAi-based therapeutic (2018). Dr. Manoharan鈥檚 invention of the N-acetylgalactosamine (GalNAc) delivery system revolutionised the field of nucleic acid-based therapeutics; six clinically approved RNA-based drugs developed at Alnylam are GalNAc conjugates.

Dr. Manoharan is an author of 259 publications and is an inventor of 318 issued U.S. patents. He has been honored with the Lifetime Achievement Award of the Oligonucleotide Therapeutics Society (2019), the 2004 American Chemical Society (ACS) Ronald Breslow Biomimetic Chemistry National Award, and the M. L. Wolfrom (2007) and D. Horton (2021) Awards from the ACS Division of Carbohydrate Chemistry. 

Mano 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 was a postdoctoral researcher at Yale University and University of Maryland (Professor John A. Gerlt).

The GalNAc-conjugated siRNAs developed at our laboratories at Alnylam are currently helping patients worldwide, and I believe that RNAi-based medicines have incredible potential. 

Muthiah Manoharan

Q&A

Can you tell us more about your work?

Prior to 1998, the only classes of medicines available were small-molecule drugs like aspirin and protein drugs like insulin. In 2003, Alnylam Pharmaceuticals was founded with the goal of harnessing a natural process known as RNA interference (RNAi) to block production of disease-causing proteins. The RNAi machinery uses short RNAs produced endogenously to guide degradation of the messenger RNAs that encode particular proteins. At Alnylam, we synthesise chemically modified versions of these short interfering RNAs (siRNAs) to take advantage of this natural mechanism. Making drugs out of siRNAs was not easy in the early 2000s. A drug must be stable, potent, and safe and must travel through the body to diseased tissues. We have now identified the types of chemical modifications that impart these drug-like properties on RNA and have also developed methods to deliver these synthetic agents to desired tissues and into cells. At Alnylam, we add 'grease balls' and/or natural sugars to deliver siRNAs to liver. Seven RNAi-based agents developed at Alnylam have now received clinical approval and are used to treat both rare diseases and cardiovascular disease. Our recent findings suggest that we will be able to develop chemistries that enable us to target siRNAs to brain, muscle, and eye to cure currently undruggable diseases.

Who or what first sparked your interest in chemistry, and how has that interest evolved over time?

When I was a student at the American College, I had great teachers including Dr. A. R. Venkitaraman, Dr. Divakar Masilamani, and others. These teachers taught chemistry with such dedication that their lectures were awe-inspiring! They ignited my interest in chemistry and insisted that there was a life beyond American College and Madurai in a place called 'America', encouraging me to take a path towards higher education. In the US, I had the opportunity to study under Professors Ernest Eliel and John Gerlt. It was John who inspired me to apply my passion for organic chemistry to the biologically relevant molecules of DNA and RNA.

What has been the most rewarding or memorable highlight of your career so far?

By far the most rewarding discovery of my career was our finding that the GalNAc ligand could be conjugated to siRNAs to enable delivery of these medicines to the liver in an active form. This conjugation results in siRNAs that can be given subcutaneously every 3 or 6 months. Meeting with the patients who tell me how these drugs are helping them have been the most rewarding moments of my career. 

What impact would you say that your work is having on your field and/or the wider world?

The GalNAc-conjugated siRNAs developed at our laboratories at Alnylam are currently helping patients worldwide, and I believe that RNAi-based medicines have incredible potential. Currently, RNAi-based drugs are used to treat both rare and prevalent diseases. Examples are GIVLAARI庐 (givosiran, approved 2019), which is used for the treatment of acute hepatic porphyria (the only approved drug available for this devastating condition that affects mainly females) and OXLUMO庐 (lumasiran, approved 2020), which treats primary hyperoxaluria type 1, which causes accumulation of oxalate stones in liver, kidney, and peripheral tissues in both pediatric and adult patients. Without treatment with OXLUMO, these patients must often have both liver and kidney transplants. AMVUTTRA庐 (vutrisiran, approved 2022 and 2025) treats both Transthyretin mediated polyneuropathy and cardiomyopathy. QFITLIA庐 (fitusiran, 2025) cures Hemophilia A and B and LEQVIO庐 (inclisiran, approved 2020) was the first RNAi-based medicine that treats a common disease (hypercholesterolemia). 

More than 50 GalNAc-conjugated siRNAs are in various stages of pre-clinical and clinical development. With so many functional proteins in the liver, which are vulnerable to cause diseases, this approach will alter the landscape of medical care with groundbreaking medicines. GalNAc conjugation results in siRNAs with long duration of action. For example, LEQVIO庐 is efficacious for up to six months.. Perhaps most importantly, GalNAc-conjugated siRNAs are given subcutaneously. This route is advantageous as drug can be self-administered. I fully expect that targeting of siRNAs to other organs will be possible in the near future. 

What future directions or opportunities do you see for your work?

Nucleic acid-based medicine helping people around the world suffering so many from difficult-to-drug disease indications.

If you had unlimited resources, what research question would you most want to explore?

I would like to explore how RNAi-based therapeutics could be used to treat mental health conditions. This would first involve identification of the genes that influence mental health, developing the drugs and administering them in a patient-friendly way. Several non-trivial problems to solve!

What is your favourite element and why?

Phosphorous. It is the phosphate linkages of DNA and RNA that make these molecules so interesting chemically and biologically.