Dear Professor Khvorova, congratulations on receiving the Else Kröner Fresenius Prize for Medical Research 2025. RNA-based therapies have made enormous progress in recent years. What kind of research findings were you able to achieve in this field?
I have studied RNAi (1) and chemical engineering for over 20 years. With Phillip Zamore (Chair & Professor at the RNA Therapeutics Institute at UMass Chan Medical School), we co-discovered rules guiding RISC loading (2) — critical for gene silencing — that informed the design of RNAi drugs, including seven for liver diseases.
However, delivering RNAi beyond the liver is a challenge. Our lab was the first to engineer lipophilicity and valency to deliver siRNAs (3) to the brain, muscle, lung, and eye. This breakthrough led to therapies for extrahepatic tissues.
Modulating gene expression in the brain allows for targeting diseases like Huntington’s, ALS, and Alzheimer’s. Chemically engineered siRNAs now offer 6–12 months of effect from a single dose and enable early intervention: in Huntington’s disease, for instance, combinatorial approaches using siRNAs may prevent disease onset entirely.
(1) RNAi (short for “RNA Interference”) is a natural mechanism of gene regulation that occurs in plant, animal and human cells. RNAi can be used to specifically suppress the production of certain proteins and enables the development of therapies for genetic diseases.
(2) RISC (short for “RNA-induced silencing complex”) is an enzyme complex that is a key player in the RNAi pathway. “Loading” refers to the process by which small RNA molecules interact with this enzyme complex.
(3) siRNA (short for “small interfering RNA”) are very short, double-stranded RNA molecules. They play a central role in RNA interference.
The prize is endowed with 2.5 million euros. What will you use the prize money for?
I am deeply grateful for this support. We will focus on advancing chemical engineering to manipulate the somatic repeat expansion (4) — a process that drives many neurodegenerative diseases like Huntington’s and may also contribute to aging. While we can currently block this process, we have yet to find a way to reverse it. Our goal is to shift the equilibrium toward repeat reduction, potentially creating short-term treatments that prevent disease before it manifests. This challenge is complex and multidimensional and requires a combination of innovative chemical engineering, a deep understanding of the underlying biology — such as mismatch repair (5) — and systematic, iterative evaluation. These kinds of ambitious projects are nearly impossible to fund through conventional means.
(4) “Somatic repeat expansion” refers to a phenomenon in which short repetitive DNA sequences grow longer and longer in somatic (non-reproductive) cells over an individual's lifetime. This phenomenon is a driver of neurodegenerative repeat expansion disorders.
(5) “Mismatch repair”: natural repair mechanism of a cell that corrects errors that occur in DNA. It’s important for genome stability and prevention of mutations
How do you see the future of RNA-based therapies with regard to previously incurable diseases?
The potential of RNA-based therapies is enormous. Different classes of RNA drugs can manipulate gene expression in virtually unlimited ways. Among them, siRNAs stand out for two key features that could fundamentally change how medicine is practiced.
First is the informational nature of siRNAs: once the chemical architecture for a target tissue is established, the sequence can be easily reprogrammed to silence any gene. This flexibility enables targeting complex, multi-gene pathways, including the mis-regulation of genetic information that results in disease.
Second, siRNAs have unprecedented durability — currently up to a year of clinical benefit from one dose — providing patient-friendly treatment options, reducing clinical burden, shifting healthcare toward prevention, and lowering costs.
Thank you for your time!