Osteogenesis imperfecta (OI) is a rare genetic bone disorder in which affected children experience severe fractures from minor impacts, leading to the colloquial term "brittle bone disease." Currently, there is a lack of specific treatment drugs for osteogenesis imperfecta. Targeted inhibition of sclerostin holds significant promise as a treatment strategy for osteogenesis imperfecta, but the sclerostin monoclonal antibody already on the market has been flagged by the U.S. FDA for cardiovascular risks, necessitating strict limitations on its use within a year. A basic research team at Hong Kong Baptist University has discovered that a specific structural domain, loop3, of the sclerostin protein does not contribute to its cardiovascular protective effects but does contribute to its inhibitory effects on bone formation (Yu et al., Nat Commun 2022; Wang et al., Theranostics 2022; Chen et al., Dis Markers 2022). Subsequently, a translational medicine team from Hong Kong Baptist University (Professor Zhang Ge from the Law Sau Fai Institute for Advancing Translational Medicine in Bone & Joint Disease, Professor Lu Aiping from the Institute of Precision Medicine and Innovative Drugs, and Professor Yu Yuanyuan from the International Cooperation Platform for Translational Medicine and Drug Discovery in the Greater Bay Area) collaborated with a clinical research team from Shanghai Jiao Tong University (Professor Zhang Zhenlin) to jointly develop a long-acting modified nucleic acid aptamer candidate drug targeting sclerostin, Apc001OA. This drug significantly promotes bone formation in an osteogenesis imperfecta animal model without causing cardiovascular risks. The long half-life of the drug is crucial for maximizing its therapeutic activity and devising highly compliant dosing regimens. The modified long-acting Apc001OA has a circulating half-life in rats of approximately 7.7 days, whereas the sclerostin monoclonal antibody already on the market has a circulating half-life in rats of 2.3 days (Ni et al., ACS Appl Mater Interfaces 2020; Yu et al., Acta Pharm Sin B 2022; Zhang et al., Front Cell Dev Bio 2022). This research received fundings from the Hong Kong Research Grants Council's Theme-based Research Scheme (T12-201/20-R), the National Key Research and Development Program of China (2018YFA0800800), the University-Industry Collaboration Programme of the Innovation and Technology Bureau of Hong Kong (UIM/298; UIM/328), and the Biomedical Incubation Programme at the Hong Kong Science Park (Aptacure). In November 2022, the Hong Kong-based startup Aptacure (www.aptacure.com) received official notification from the U.S. Food and Drug Administration (FDA) that the long-acting modified Apc001OA had been granted Rare Pediatric Disease designation (RPD-2022-667) and Orphan Drug designation (DRU-2022-9087). This marks the first nucleic acid aptamer drug developed in Hong Kong to receive FDA Rare Pediatric Disease designation and the first nucleic acid aptamer drug in China to receive this designation (PCT/CN2019/074764: China CN201980012952.6, Hong Kong HK40038022A, Europe EP3754021A1, United States US20210198672A1, Japan JP2021513365A; PCT/CN2022/082996).

Rare Pediatric Disease Designation (RPDD) refers to drugs being developed to treat rare diseases in children. Obtaining RPDD means that if the drug is initially approved for clinical use in the rare pediatric disease, the applicant is entitled to receive a Pediatric Rare Disease Priority Review Voucher (PRV). The PRV allows the holder to expedite the review of a new drug application by six months (normally 12 months), and the six-month acceleration in regulatory review could have significant economic value. Additionally, PRVs are marketable, with historical transaction prices exceeding $100 million.

References

1. Yu, Y., Wang, L., Ni, S., Li, D., Liu, J., Chu, HY., Zhang, N., Sun, M., Li, N., Ren, Q., Zhuo, Z., Zhong, C., Xie, D., Li, Y., Zhang, Z., Zhang, H., Li, M., Zhang, Z., Chen, L., Pan, X., Xia, W., Zhang, S., Lu, AP., Zhang, BT., Zhang G. Targeting sclerostin loop3 maintains the protective effect of sclerostin on cardiovascular system but attenuates the inhibitory effect of sclerostin on bone formation. Nat Commun. 13(1), 1-16.

2. Wang, L., Yu, Y., Ni, S., Li, D., Liu, J., Xie, D., Chu, HY., Ren, Q., Zhong, C., Zhang, N., Li, N., Sun, M., Zhang, Z., Zhuo, Z., Zhang, H., Zhang, Shu., Li, M., Xia, W., Zhang, Z., Chen, L., Shang, P., Pan, X., Lu, AP., Zhang, BT., Zhang G. Therapeutic aptamer targeting sclerostin loop3 for promoting bone formation without increasing cardiovascular risk in osteogenesis imperfecta mice. Thearanostics. 12(13), 5645.

3. Chen L, Gao G, Shen L, Yue H, Zhang G, Zhang Z. Serum Sclerostin and Its Association with Bone Turnover Marker in Metabolic Bone Diseases. Dis Markers. 10;2022:7902046.

4. Ni, S., Zhuo, Z., Pan, Y., Yu, Y., Li, F., Liu, J., Wang, L., Wu, X., Li, D., Wan, Y., Zhang, L., Yang, Z., Zhang, BT. & Zhang, G. (2020). Recent progress in aptamer discoveries and modifications for therapeutic applications. ACS Appl Mater Interfaces 13: 9500-9519.

5. Yu, S., Li, D., Zhang, N., Ni, S., Sun, M., Wang, L., Xiao, H., Liu, D., Liu, J., Yu, Y., Zhang, Z., Yang, SYY., Zhang, S., Lu, A., Zhang, Z., Zhang, BT. & Zhang, G. (2022). Drug discovery of sclerostin inhibitors. Acta Pharm Sin B. 12(5):2150-2170.

6. Zhang, Y., Zhang, H., Chan, D W H., Ma, Y., Lu, A., Yu, S., Zhang, B., Zhang, G. (2022) Strategies for developing long-lasting therapeutic nucleic acid aptamer targeting circulating protein: the present and the future. Front Cell Dev Biol. 10:1048148.