Anastasia Khvorova

Anastasia Khvorova is the world's foremost authority on the chemistry and biology of small interfering RNA (siRNA) for in vivo therapeutic applications. As Professor at the University of Massachusetts Chan Medical School and Co-Director of the RNA Therapeutics Institute, she has defined the chemical modification rules that enable siRNAs to function safely and durably as drugs in living organisms. Khvorova's laboratory pioneered systematic chemical modification of siRNA duplexes to achieve metabolic stability, reduced immunostimulation, and favorable biodistribution. Her research demonstrated that fully chemically modified siRNAs — incorporating 2'-fluoro (2'-F) and 2'-O-methyl (2'-OMe) modifications in a defined alternating pattern — maintain full RNAi potency while gaining months-long stability in biological fluids. These insight generated by her lab formed the chemical foundation for all current clinical siRNA drug candidates. A major focus of Khvorova's research is the challenge of delivering siRNA to organs beyond the liver. While GalNAc-siRNA conjugates have succeeded magnificently for hepatic targets, the brain represents one of the most formidable barriers in drug delivery. Khvorova's group systematically characterized how chemical modification patterns, lipid conjugation strategies, and molecular geometry affect siRNA transport across the blood-brain barrier and distribution within brain parenchyma following intrathecal administration. Her laboratory developed divalent siRNA architectures (Di-siRNA) connected by flexible linkers that achieve widespread cortical and striatal distribution after a single cerebrospinal fluid injection — an approach with direct application to glioblastoma and brain metastasis. For liver targets relevant to cancer biology — including oncogenic signaling molecules, DNA damage repair factors, and immunosuppressive cytokines produced by the liver — Khvorova's group has refined GalNAc-siRNA conjugate design to maximize potency, duration of effect, and safety margin. Her work on siRNA strand asymmetry — demonstrating that rational manipulation of the thermodynamic profile of siRNA duplexes controls which strand is loaded into RISC — has been translated directly into improved clinical siRNA design. Khvorova has co-founded multiple biotechnology companies based on her laboratory's technologies and serves as a scientific advisor to leading RNA medicine companies. She is a member of the National Academy of Inventors.

Anastasia Khvorova 是全球最权威的体内治疗性小干扰RNA（siRNA）化学与生物学专家。作为马萨诸塞大学陈医学院RNA治疗研究所联合主任，她定义了使 siRNA 在活体中安全、持久发挥药物作用的化学修饰规则。 她的实验室率先系统性地对 siRNA 双链进行化学修饰（2'-F 和 2'-OMe 交替修饰），实现了数月级别的生物液体稳定性，同时保持全效 RNAi 活性，为当前所有临床 siRNA 药物候选分子奠定了化学基础。 在脑部递送领域，她开发的二价 siRNA（Di-siRNA）架构经单次脑脊液注射即可在皮层和纹状体实现广泛分布，对胶质母细胞瘤和脑转移瘤治疗具有直接应用价值。她关于 siRNA 链不对称性的研究也直接转化为改进的临床 siRNA 设计规则。