A Big Clinical Challenge: The marketed humanized therapeutic sclerostin antibody Romosozumab shows an osteoanabolic potential in patients with postmenopausal osteoporosis, resulting in a significant reduction in fracture risk. However, severe cardiovascular events were found in phase III clinical trials (BRIDGE and ARCH) of the Romosozumab for treatment of postmenopausal osteoporosis. Hence, Romosozumab for postmenopausal osteoporosis was approved by the U.S. Food and Drug Administration (U.S. FDA) with a black-boxed warning on the risk of heart attack, stroke and cardiovascular death, while it was approved by European Medicines Agency (EMA) with restriction to severe postmenopausal osteoporosis who had no disease history of heart attack and stroke. For a novel osteogenic therapy for chronic diseases, it would be better if serious cardiovascular risks could be avoided. Accordingly, it is desirable to develop a next generation of sclerostin inhibitor to promote bone formation without increasing cardiovascular risk.

Molecular Target Study: A multidisciplinary joint research team [Prof. ZHANG Ge, Law Sau Fai Institute for Advancing Translational Medicine in Bone&Joint Diseases, Hong Kong Baptist University (HKBU); Assistant Professor YU Yuanyuan, HKBU, Guangdong-Hong Kong-Macao Greater Bay Area International Collaboration Platform on Fitting Ligand Translational Medicine and Drug Discovery; Prof. LU Aiping, Member of the European Academy of Sciences, Institute of Integrative Bioinformatics Medicine and Translational Science, HKBU Laboratory of Computational Medicine; Prof. ZHANG Baoting, School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong] firstly found that sclerostin loop3 contributed to the antagonistic effect of sclerostin on bone formation, while the protective effect of sclerostin on cardiovascular system was independent of sclerostin loop3 [The relevant research was supported by Theme-based Research Scheme (T12-201/20-R), General Research Fund (GRF12102120, GRF12100921), and the National Natural Science Foundation of China under the Youth Fund (NSFC81601929)]. This discovery provides direction for the discovery of critical molecular targets for a new generation of sclerostin inhibitor drugs to address the clinical challenge of cardiovascular safety faced by sclerostin monoclonal antibodies in osteogenic therapy (Link to the paper: https://www.nature.com/articles/s41467-022-31997-8).

Aptamer Drug Discovery: Osteogenesis imperfecta (OI, also known as glass dolls or porcelain dolls) is a rare genetic bone disease for which there is a lack of effective therapeutic drugs. Both genetic and pharmacological data suggests that sclerostin is an effective molecular target in bone formation in OI. Therefore, in collaboration with Aptacure Therapeutics Limited, (a company funded by the Biomedical Incubation Programme of the Hong Kong Science Park, http://www.aptacure.com/), the joint research team used the innovative artificial intelligence-assisted high-throughput aptamer screening and synthetic modification technologies established at the Hong Kong International Genome Research Centre of HKBU to screen and synthesise the nucleic acid aptamer Apc001 specifically targeting sclerostin loop 3 (PCT No.: PCT/CN2019/074764. PCT Pub No.: WO2019/154410) based on the above results. Morover, the joint research team validated the therapeutic effect of Apc001 in OI mice (the relevant studies were supported by University-Industry Collaboration Funds UIM/298 and UIM/328 funded by the Innovation and Technology Commission of Hong Kong, the Special Funds for Key Research and Development Programmes of the Ministry of Science and Technology of China, 2018YFA0800800 2018YFA0800800, and Applied Basic Research Fund for Key Projects of Guangdong Province 2019B1515120089). The results showed that  the sclerostin loop3-specific aptamer could promote bone formation, increase bone mass, and improve bone microarchitecture integrity in OI mice, while had no influence in the cardiovascular events progression in the mouse model of cardiovascular disease (Figure 1). (Link to the paper: https://www.thno.org/v12p5645.htm).

U.S. FDA Orphan Drug Designation: FDA Orphan Drug Designation: A spokesman from Aptacure Therapeutics Limited has been working closely with a joint research team led by HKBU under the funding of the Biomedical Incubation Programme of Hong Kong Science Park. An independent third-party toxicological study revealed no abnormalities in the histopathological examination of major organs of all the animals receiving Apc001 at the maximum exploratory dose. Moreover, another company-commissioned study demonstrated that 12-week treatment of the long-acting dosage form of Apc001 (Apc001OA) promoted bone formation, increased bone mass and improved bone microarchitecture in OI mice (Figure 2). Currently, Apc001 for the treatment of OI has been granted Orphan Drug Designation by the U.S. FDA (FDA No. DRU-2019-6966), which is the first novel drug in Hong Kong to be granted Orphan Drug Designation by the U.S. FDA. The Company is preparing for the start-up into the pilot phase for the active promotion of the US-China dual reporting process for Apc001OA. Basic research on the expansion of Apc001 indications is also being planned by the joint research team with HKBU.

Government-Industry-University-Research Co-innovation: Promoted by the Knowledge Transfer Office of HKBU, the joint research team led by HKBU and Aptacure Therapeutics Limited is committed to addressing unmet clinical needs, from basic research on molecular target function, to drug discovery and disease translation, to FDA Orphan Drug designation, which embodies an organic and collaborative innovation model that makes full use of the resources of the government, industry, academia, and research institutions in the optimal allocation of the resources between the University and the enterprises, and establishes a sustainable research and development pathway.

Figure 1: Schematic diagram of molecular mechanism: Targeting sclerostin loop3 preserves its cardiovascular protective action and promotes bone formation

Figure 2: The effect of Apc001 long-acting dosage form administration for 12 weeks on distal femur bone volume and bone structure in osteogenesis imperfecta mice: micro-CT reconstructed three-dimensional trabecular bone representative pictures of the Apc001 group and vehicle group; scale bar: 1 mm.

Reference (^#Co-first author; *co-corresponding author)

1. Yu, S.^#, Li, D.^#, Zhang, N.^#, Ni, S., Sun, M., Wang, L., Xiao, H., Liu, D., Liu, J., Yu, Y., Zhang, Z., Yeung, S. T. Y., Zhang, S., Lu, A., Zhang, Z.*, Zhang, B.* & Zhang, G.*, Drug discovery of sclerostin inhibitors. Acta Pharmaceutica Sinica B. 12, 5, 2150-2170 (2022). (IF: 11.413)

2. Yu, Y.^#*, Wang, L.^#, Ni, S^#, Li, D., Liu, J., Chu, H.Y., Zhang, N., Ren, Q., Zhuo, Z., Zhong, C., Xie, D., Li, Y., Zhang, Z.K., Zhang, H., Li, M., Zhang Z., Chen L., Pan, X., Xia, W., Zhang, S., Lu, A.*, Zhang, B.T.* & Zhang, G*. Targeting loop3 of sclerostin preserves its cardiovascular protective action and promotes bone formation. Nature Communications (2022) In press. (IF: 17.69)

3. Wang, L.^#, Yu, Y. ^# *, Ni, S,^# Li, D., Liu, J., Xie, D., Chu, H.Y., Ren, Q., Zhong, C., Zhang, N., Li, N., Sun, M., Zhang, Z.K., Zhuo, Z., Zhang, H., Zhang, S., Li, M., Xia, W., Zhang Z., Chen L., Shang, P., Pan, X., Lu, A.*, Zhang, B.T.* & Zhang, G*. Therapeutic aptamer targeting sclerostin loop3 for promoting bone formation without increasing cardiovascular risk in osteogenesis imperfecta mice. Theranostics (2022) In press. (IF: 11.60)