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.  

Professor ZHANG Ge qualified his M.D. under the joint translational orthopaedic medicine program of Chinese University of Hong Kong and Shanghai University of Chinese Medicine. Prof. Zhang Ge has been working on biomedicine in bone and cardiovascular diseases, aptamer-based translational medicine and drug discovery for more than ten years. He has published a series of high-impact journal publications in Nature Medicine, Nature Communication, Biomarterials, Arthritis & Rheumatism, and Theranostics, etc. Nature Reviews Rheumatology (J. H. Duarte, Nature Reviews Rheumatology, 2015) and Nature Reviews Endocrinology (J. Sargent, Nature Reviews Endocrinology, 2015) praised his work to accelerate clinical translation of nucleic acid interference strategies. Nature Review Drug Discovery (Zhou J et al., Nature Review, 2016) evaluated his work as a driving force for future development and clinical evaluation of aptamers. Recently, his supervised team discovered that sclerostin participated in protecting cardiovascular system and inhibiting bone formation via different loops. Sclerostin loop3 played an important role in the antagonistic effect of sclerostin on bone formation, while the cardiovascular protective effect of sclerostin was independent of loop3 (Yu Y et al., Nature Communication, 2022). Further, one therapeutic sclerostin loop3 aptamer for osteogenesis imperfecta was screened to promote bone formation without increasing cardiovascular risk (Wang L et al., Theranostics, 2022), which was granted Orphan Drug Designation and Rare Pediatric Disease Designation by US Food and Drug Administration (DRU-2019-6966; RPD-2022-667).

Aptamer-based targeted delivery system 

Currently, major bottleneck for many drug candidates to achieve therapeutic potential is lack of in vivo targeted delivery systems. Up till now, Prof. Zhang Ge has developed two generations of aptamer-based osteoblast targeting delivery systems (G. Zhang et al., Nat Med, 2012; C. Liang et al., Nat Med, 2015), one generation of aptamer-based osteoclast targeting delivery system (J. Liu et al., Biomaterials, 2015), and one generation of aptamer-based osteosarcoma targeting delivery system (C. Liang et al., Biomaterials, 2017). 

Two osteoblast targeting delivery systems to promote clinical translation of nucleic acid interference strategies in treating bone-related diseases: A review published in Nature Medicine evaluated the first generation of osteoblast 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 remodeling unit (C. J. Rosen, Nat Med, 2012). Utilizing the first generation of osteoblast targeting delivery system, the role of miR-214 in regulating bone formation for ameliorating osteoporosis, the role of osteoblastic CKIP-1 in inhibiting bone formation during aging and in regulating joint inflammation of rheumatoid arthritis were further identified by Prof. Zhang Ge (X. Wang et al., Nat Med, 2013; J. Liu et al., Aging Cell, 2017; X. He et al., EBioMedicine, 2019). 

Nature Reviews Rheumatology and Nature Reviews Endocrinology made special comments on the second generation of osteoblast delivery system, praising the work to accelerate clinical translation of nucleic acid interference strategies for bone disorders (J. H. Duarte, Nat Rev Rheumatol, 2015; J. Sargent, Nat Rev Endocrinol, 2015). A review published in Nature Review Drug Discovery evaluated the work as a driving force for future development and clinical evaluation of aptamers (J. Zhou and J. Rossi, Nat Rev Drug Discov, 2017). In China “Tian Zhou-1” cargo spacecraft project, the second generation of osteoblast targeting delivery system facilitated investigating the molecular mechanism underlying space microgravity-induced bone loss in astronauts during deep space exploration (http://tv.cctv.com/2017/07/02/VIDEda0AfwqofJz2wZvQAUdO170702.shtml).

Osteoclast targeting delivery system to facilitate clinical translation of microRNA modulators in treating osteoclast-dysfunction-induced skeletal diseases: The aptamer-based osteoclast delivery system dramatically reduced the therapeutic concentration of intravenously administrated micro RNA by 10 times, while extended dosing interval by 1.5 times (J. Liu et al., Biomaterials, 2015).

Employing this osteoclast targeting delivery system, the role of osteoclast-derived exosomal miR-214 in regulating osteoblastic bone formation was further identified by Prof. Zhang Ge (D. Li et al., Nat Commun, 2016).

Osteosarcoma targeting delivery system, which promoted the clinical translation of CRISPR/Cas9 genome editing technology: For the first time, intravenously administrated CRISPR/Cas9 plasmids were selectively delivered to osteosarcoma cells in both orthotropic osteosarcoma and lung metastasis by osteosarcoma targeting delivery system (C. Liang et al., Biomaterials, 2017).

Therapeutic aptamer

A therapeutic aptamer against sclerostin loop3, which has been granted orphan drug designation by the US FDA: Therapeutic antibody against sclerostin (Romosozumab) for reversing postmenopausal osteoporosis was approved by US FDA with a boxed warning on cardiovascular risk, whereas was rejected by European Medicines Agency due to cardiovascular risk in July 2019. Prof. Zhang Ge found that both loop2 and loop3 in sclerostin played important roles in inhibiting osteogenesis, whereas only sclerostin loop2 had protective effect on cardiovascular system. From basic science towards translational medicine, Prof Zhang Ge has designed the second generation of sclerostin inhibitor selectively targeting loop3 for bone anabolism with low cardiovascular safety concern for postmenopausal osteoporosis and osteogenesis imperfecta (OI). OI is a dominantly inherited skeletal rare disease, without pharmacological therapy specifically developed for OI patients. This therapeutic aptamer for OI has been granted orphan drug designation by the US FDA in 2019 (DRU-2019-6966) and Rare Pediatric Disease Designation in 2022 (RPD-2022-667). 

Aptamer-drug conjugates

A smart aptamer-paclitaxel conjugate, which is expected to be the next generation of innovative drugs for cancer treatment: The nucleolin aptamer facilitated the uptake of paclitaxel specifically in tumor cells, subsequently resulting in notably improved antitumor activity and reduced toxicity (F. Li et al., Nat Commun, 2017). Increase Innovative Medicine Pharmaceutical Company has cooperated with Prof. Zhang Ge and invested 10 million HKD to establish research center for further investigation on this highly water-soluble nucleolin aptamer-paclitaxel conjugate (NucA-PTX).

An aptamer-Smurf1 inhibitor conjugate to provide precision medicine-based bone anabolic strategy for age-related osteoporosis: The osteoblast aptamer facilitated the development of the precision medicine-based bone anabolic strategy for the BMP-2n/Smurf1e osteoporosis, one major subgroup of age-related osteoporosis which showed poor response to recombinant human BMPs (rhBMPs-2) during spinal fusion (C. Liang et al., Nat Commun, 2018). HP Precision Medicine Ltd. Co. has cooperated with Prof. Zhang Ge and invested 2 million HKD to initiate further research on this osteoblast aptamer-Smurf1 inhibitor conjugate.