David R. Corey

David Corey is a chemist and pharmacologist at UT Southwestern Medical Center whose four-decade career has pioneered the application of synthetic nucleic acid chemistry — particularly peptide nucleic acids (PNAs) and chemically modified oligonucleotides — to regulate gene expression at multiple levels, including translational regulation, RNA structure targeting, and the little-understood nuclear RNAi pathway. Corey made early foundational contributions to PNA biology. Peptide nucleic acids are synthetic DNA/RNA analogs in which the negatively charged phosphodiester backbone is replaced by an uncharged N-(2-aminoethyl)glycine polymer, enabling PNAs to bind complementary nucleic acid sequences with extraordinary affinity and sequence selectivity, and to resist nuclease degradation completely. Corey's laboratory characterized the cellular uptake, nuclear penetration, and gene regulation capabilities of PNA molecules targeting coding and non-coding RNAs, establishing their utility as research tools and potential therapeutic agents. His work demonstrated that PNAs can invade duplex DNA at purine-rich sequences to form stable strand-invasion complexes, enabling direct genome-level gene regulation without requiring protein cofactors. Corey's most significant intellectual contribution to cancer RNA biology has been the systematic investigation of how synthetic oligonucleotides introduced into cell nuclei can regulate gene expression through endogenous nuclear RNA regulatory pathways. His laboratory discovered that short duplex RNAs and single-stranded antisense oligonucleotides targeting promoter-associated non-coding RNAs or RNA polymerase II transcripts in the nucleus can activate or silence gene expression through nuclear Argonaute 2-dependent mechanisms — a phenomenon he termed RNA activation (RNAa) and nuclear RNAi. These findings revealed that the RNAi machinery is not restricted to the cytoplasm but operates in the nucleus to regulate gene transcription, expanding the targetable sequence space for RNA therapeutics. In cancer applications, Corey's laboratory has targeted oncogenic non-coding RNAs including MALAT1, NEAT1, and the long non-coding RNA HOTAIR — which is overexpressed in multiple cancers and promotes metastasis — using antisense gapmers and splice-switching oligonucleotides. His group demonstrated that ASO-mediated depletion of nuclear lncRNAs can restore expression of tumor suppressor genes silenced by lncRNA-directed chromatin remodeling, offering a novel mechanism-based approach to cancer therapy. He has also applied PNAs to block RNA secondary structures that protect oncogenic mRNAs from translation inhibition, demonstrating sequence-specific translational de-repression. Corey is a fellow of the American Chemical Society and has authored more than 300 peer-reviewed publications spanning chemical biology, nucleic acid therapeutics, and cancer RNA biology.

David Corey 是德克萨斯大学西南医学中心的化学家兼药理学家，四十年职业生涯中先后开拓了肽核酸（PNA）和化学修饰寡核苷酸在多个层面调控基因表达的应用——包括翻译调控、RNA结构靶向，以及知之甚少的核内RNAi通路。 他对PNA生物学做出了早期奠基性贡献：PNA以不带电荷的N-(2-氨乙基)甘氨酸聚合物骨架取代磷酸二酯骨架，对互补核酸序列具有极高亲和力和序列选择性，并完全抵抗核酸酶降解。他最重要的智识贡献是系统研究了引入细胞核内的合成寡核苷酸如何通过内源性核内RNA调控通路（即RNA激活/RNAa 和核内RNAi）来调节基因表达，揭示了RNAi机器并不局限于细胞质，而是在细胞核内运行以调控基因转录。在癌症应用中，他靶向 MALAT1、NEAT1、HOTAIR 等致癌长链非编码RNA，证明 ASO 介导的核内 lncRNA 耗竭可恢复被 lncRNA 引导的染色质重塑所沉默的肿瘤抑制基因的表达。