John J. Rossi

John Rossi is one of the founding pioneers of therapeutic RNA, with a career spanning more than four decades at City of Hope Comprehensive Cancer Center that bridged the earliest discoveries in ribozyme biology through the development of RNA interference and RNA aptamer-based cancer targeting strategies. His laboratory established foundational principles for using catalytic RNAs, siRNAs, and RNA aptamers as therapeutic modalities against cancer and viral diseases. In the early 1990s, Rossi was among the first to develop ribozymes — catalytic RNA molecules — as gene-silencing agents for HIV-infected cells. His laboratory designed hammerhead and hairpin ribozymes targeting HIV RNA sequences and demonstrated their ability to suppress viral replication in primary human CD4+ T cells and hematopoietic progenitors, advancing the first ribozyme-based gene therapy into clinical trial. This work established the precedent for RNA-based gene therapy in infectious disease and cancer. With the discovery of RNA interference, Rossi's group rapidly pivoted to exploit Dicer-substrate siRNAs (DsiRNAs) — 27-mer RNA duplexes processed by Dicer into active siRNA — which his laboratory showed are substantially more potent than conventional 21-mer siRNAs for gene silencing. This mechanistic insight, rooted in understanding the RISC loading pathway, improved the efficiency of RNAi-based cancer gene knockdown significantly. Rossi's most innovative contribution to cancer therapy is the RNA aptamer-siRNA chimera platform. His laboratory developed aptamers that bind with high affinity and selectivity to prostate-specific membrane antigen (PSMA), a cell surface receptor overexpressed on prostate cancer cells and the neovasculature of many solid tumors. By covalently linking PSMA-targeting aptamers to siRNA cargo molecules targeting oncogenes (PLK1, BCL2, VEGF), his group demonstrated cell-type-selective siRNA uptake, RISC loading, and potent cancer-specific gene silencing both in vitro and in vivo without systemic toxicity. This aptamer-siRNA chimera strategy provided a compelling proof of concept for targeted RNA interference therapy in solid tumors, directly addressing the fundamental challenge of selective cancer cell delivery. Rossi's laboratory also explored the use of RNA aptamers as antagonists of cancer cell surface receptors, blocking ligand binding and downstream signaling independently of their delivery function. He contributed extensively to understanding DICER1 biology and miRNA processing in cancer contexts.

John Rossi 是治疗性RNA领域的奠基先驱之一，在希望之城综合癌症中心工作四十余年，从最早的核酶生物学发现，到RNA干扰和RNA适配体癌症靶向策略的开发，跨越了RNA治疗学的多个时代。 他在1990年代率先开发以核酶为基础的HIV基因沉默疗法，推动了首个核酶基因治疗临床试验。随后，他系统研究了 Dicer 底物 siRNA（DsiRNA）——27聚体RNA双链，证明其基因沉默效力显著优于常规21聚体 siRNA。 Rossi 对癌症治疗最具创新性的贡献是 RNA 适配体-siRNA 嵌合体平台：他开发了高亲和力靶向前列腺特异性膜抗原（PSMA）的适配体，与靶向癌基因的 siRNA 共价连接，在体内外均实现了癌细胞选择性 siRNA 摄取和基因沉默，为实体瘤靶向 RNAi 治疗提供了令人信服的概念验证。