Therapeutic aptamer targeting sclerostin loop3 for promoting bone formation without increasing cardiovascular risk in osteogenesis imperfecta mice

Wang, Luyao1,2,3,4,5; Yu, Yuanyuan1,2,3,4,5; Ni, Shuaijian1,2,3,4; Li, Dijie1,2,3,4; Liu, Jin1,2,3,4; Xie, Duoli1,2,3,4; Chu, Hang Yin2,6; Ren, Qing1,2,3,4; Zhong, Chuanxin1,2,3,4,7; Zhang, Ning2,6; Li, Nanxi1,2,3,4; Sun, Meiheng1,2,3,4; Zhang, Zong-Kang2,6; Zhuo, Zhenjian2,6; Zhang, Huarui1,2,3,4; Zhang, Shu8; Li, Mei9; Xia, Weibo9; Zhang, Zhenlin10; Chen, Lin11; Shang, Peng5; Pan, Xiaohua12; Lu, Aiping1,2,3,4,5; Zhang, Bao-Ting2,6; Zhang, Ge1,2,3,4,5

2022

10.7150/thno.63177

Theranostics   Impact Factor & Quartile

1838-7640

["Rationale: Sclerostin inhibition demonstrated bone anabolic potential in osteogenesis imperfecta (OI) mice, whereas humanized therapeutic sclerostin antibody romosozumab for postmenopausal osteoporosis imposed clinically severe cardiac ischemic events. Therefore, it is desirable to develop the next generation sclerostin inhibitors to promote bone formation without increasing cardiovascular risk for OI.","Methods and Results: Our data showed that sclerostin suppressed inflammatory responses, prevented aortic aneurysm (AA) and atherosclerosis progression in hSOST(ki).Col1a2(+/)(G610C).ApoE(-/- )mice. Either loop2&3 deficiency or inhibition attenuated sclerostin's suppressive effects on expression of inflammatory cytokines and chemokines in vitro, whilst loop3 deficiency maintained the protective effect of sclerostin on cardiovascular system both in vitro and in vivo. Moreover, loop3 was critical for sclerostin's antagonistic effect on bone formation in Col1a2(+/)(G610C) mice. Accordingly, a sclerostin loop3-specific aptamer aptscl56 was identified by our lab. It could recognize both recombinant sclerostin and sclerostin in the serum of OI patients via targeting loop3. PEG40k conjugated aptscl56 (Apc001PE) demonstrated to promote bone formation, increase bone mass and improve bone microarchitecture integrity in Col1a2(+/)(G610C) mice via targeting loop3, while did not show influence in inflammatory response, AA and atherosclerosis progression in Col1a2(+/)(G610C).ApoE(-/-) mice with Angiotensin II infusion. Further, Apc001PE had no influence in the protective effect of sclerostin on cardiovascular system in hSOST(ki).Col1a2(+/)(G610C).ApoE(-/- ) mice, while it inhibited the antagonistic effect of sclerostin on bone formation in hSOST(ki).Col1a2(+/)(G610C) mice via targeting loop3. Apc001PE was non-toxic to healthy rodents, even at ultrahigh dose. Apc001PE for OI was granted orphan drug designation by US-FDA in 2019 (DRU-2019-6966).","Conclusion: Sclerostin loop3-specific aptamer Apc001PE promoted bone formation without increasing cardiovascular risk in OI mice."]

Aptamer sclerostin loop3 osteogenesis imperfecta bone formation no cardiovascular risk no toxicity

SCI

English

Others

National Key R&D Program from the Ministry of Science and Technology of China[2018YFA0800800] ; Hong Kong General Research Fund from the Research Grants Council of the Hong Kong Special Administrative Region, China["12102120","12114416","12103519","12136616","14103420","14103121","14109721"] ; Theme -based Research Scheme from the Research Grants Council of the Hong Kong Special Administrative Region, China[T12 -201/20-R] ; Basic and Applied Basic Research Fund from Department of Science and Technology of Guangdong Province[2019B1515120089] ; Inter -institutional Collaborative Research Scheme from Hong Kong Baptist University[RC-ICRS/19-20/01] ; University -Industry Collaboration Programme from Innovation and Technology Commissions of the Hong Kong Special Administrative Region, China["UIM/328","UIM/298"]

Research & Experimental Medicine

Medicine, Research & Experimental

WOS:000829099700012

IVYSPRING INT PUBL

Web of Science

1.Hong Kong Baptist Univ, Sch Chinese Med, Law Sau Fai Inst Adv Translat Med Bone & Joint Di, Hong Kong, Peoples R China
2.Guangdong Hong Kong Macao Greater Bay Area Int Re, Hong Kong, Peoples R China
3.Hong Kong Baptist Univ, Sch Chinese Med, Inst Precis Med & Innovat Drug Discovery PMID, Hong Kong, Peoples R China
4.Hong Kong Baptist Univ, Sch Chinese Med, Inst Integrated Bioinformed & Translat Sci IBTS, Hong Kong, Peoples R China
5.Northwestern Polytech Univ Hong Kong Baptist Univ, Shenzhen, Peoples R China
6.Chinese Univ Hong Kong, Fac Med, Sch Chinese Med, Hong Kong, Peoples R China
7.Southern Univ Sci & Technol, Dept Mat Sci & Engn, Shenzhen, Peoples R China
8.Air Force Med Univ, Key Lab Aerosp Med, Minist Educ, Xian, Shaanxi, Peoples R China
9.Chinese Acad Med Sci & Peking Union Med Coll, Peking Union Med Coll Hosp, Dept Endocrinol, Natl Hlth Commiss,Key Lab Endocrinol, Beijing, Peoples R China
10.Shanghai Jiao Tong Univ Affiliated Peoples Hosp 6, Shanghai Clin Res Ctr Bone Dis, Dept Osteoporosis & Bone Dis, Shanghai, Peoples R China
11.Army Med Univ, Daping Hosp, Trauma Ctr,State Key Lab Trauma Burns & Combined, Res Inst Surg,Dept Wound Repair & Rehabil Med, Chongqing, Peoples R China
12.Shenzhen Univ, Shenzhen Baoan Peoples Hosp, Affiliated Hosp 2, Orthoped Ctr, Shenzhen, Peoples R China

Wang, Luyao,Yu, Yuanyuan,Ni, Shuaijian,et al. Therapeutic aptamer targeting sclerostin loop3 for promoting bone formation without increasing cardiovascular risk in osteogenesis imperfecta mice[J]. Theranostics,2022,12(12).

Wang, Luyao.,Yu, Yuanyuan.,Ni, Shuaijian.,Li, Dijie.,Liu, Jin.,...&Zhang, Ge.(2022).Therapeutic aptamer targeting sclerostin loop3 for promoting bone formation without increasing cardiovascular risk in osteogenesis imperfecta mice.Theranostics,12(12).

Wang, Luyao,et al."Therapeutic aptamer targeting sclerostin loop3 for promoting bone formation without increasing cardiovascular risk in osteogenesis imperfecta mice".Theranostics 12.12(2022).