Drug discovery

Professor Zhang Ge has devoted himself to aptamer-based translational medicine and drug discovery at the following three aspects, where the wisdom of traditional Chinese medicine meets modern science and technology. 

For aptamer-based targeted delivery towards translational medicine, Professor Zhang has identified an oligopeptide aptamer approaching bone formation surface (the first generation of osteoblast-target moiety) (Zhang G, et al, Nature Medicine, 2012; Wang X, et al, Nature Medicine, 2013) and a nucleic acid aptamer targeting osteoblast (the second generation of osteoblast-target moiety) (Liang Chao, et al, Nature Medicine, 2015). A review published in Nature Medicine evaluated the first-generation osteoblast-targeted delivery system as the first work to successfully package and administer siRNAs to therapeutically target the skeleton, leading to additional new strategies for targeting the skeletal remodelling unit (C. J. Rosen.  Nature Medicine, 2012). Nature Reviews Rheumatology and Nature Reviews Endocrinology made special comments on the second generation of osteoblast-target moiety, praising the work to accelerate the clinical translation of nucleic acid interference strategies for bone disorders (J. H. Duarte. Nature Reviews Rheumatology, 2015; J Sargent, Nature Reviews Endocrinology, 2015). Nature Review Drug Discovery also evaluated the work as a driving force for future development and clinical evaluation of aptamers (J. Zhou. Nature Review Drug Discovery, 2017). In China, the Tian Zhou-1 cargo spacecraft project, the second generation of osteoblast-target moiety, facilitated the investigation of the molecular mechanism underlying space microgravity-induced bone loss in astronauts during deep space exploration.

In addition, Professor Zhang has identified an oligopeptide aptamer approaching bone resorption surface – the first generation of osteoclast-target moiety, (Li D, et al, Nature Communication, 2016; Liu J, et al, Biomaterial, 2015) – and a nucleic acid aptamer targeting osteosarcoma cells (osteosarcoma-target moiety) (Liang Chao, et al, Biomaterial, 2017). Asia Research News evaluated the osteosarcoma-target moiety to pave the way for new clinical approaches using the CRISPR/Cas9 gene editing technology in cancer treatment (Asia Research News Magazine, 2019).

For aptamer-drug conjugates toward precision medicine, Professor Zhang has developed an osteoblast oligopeptide aptamer-chalcone conjugate to facilitate the conjugated herbal natural product chalcone to target osteoblast for promoting bone formation in BMP-treatment non-responders during spinal fusion (Liang Chao, et al, Nature Communication, 2018). He has also further developed a tumor cell aptamer-Paclitaxel (natural product) conjugate with high water solubility to facilitate the conjugated Paclitaxel to target tumour cells with low systemic toxicity in ovarian cancer – a precision medicine-based personalised Paclitaxel for specific cancer types (Li F, et al, Nature Communication, 2017).  

For therapeutic aptamers, Professor Zhang has found that sclerostin loop 3 truncation can promote bone anabolic Wnt signalling and bone formation but has no influence on the protection effect of sclerostin in the cardiovascular system. It guides drug discovery direction to address the clinical challenge (a cardiovascular safety concern) of the marked sclerostin antibody in osteoporosis treatment.  Further, Professor Zhang has identified an aptamer functionally targeting sclerostin loop 3 (the second generation of sclerostin inhibitor) to promote bone anabolism with low cardiovascular concern for bone anabolic therapy in osteoporosis and osteogenesis imperfect (PCT No.: PCT/CN2019/074764. PCT Pub No.: WO2019/ 154410. PCT Pub Date: 15 August 2019). The therapeutic aptamer was granted Orphan Drug Designation by the US Food and Drug Administration (FDA, DRU-2019-6966) in 2019.