New aptamer drug for bone anabolic therapies

New aptamer drug for bone anabolic therapies

Graphically Abstract. Credit: theranostics (2022). DOI: 10.7150/thno.63177

A research team led by Hong Kong Baptist University (HKBU) has identified a molecular target for anabolic bone therapies using a selected aptamer that acts as an inhibitor of sclerostin, a protein that prevents bone growth. The discovery offers hope for the development of an effective next-generation treatment for osteoporosis and osteogenesis imperfecta that is free of cardiovascular risk compared to the commercialized antibody drug.

The results of the research have been published in the journals nature communications Y theranostics. The new drug is in the preclinical trial development stage and the research team plans to begin clinical trials in the US and on the mainland in 2024.

Current medication increases cardiovascular risk

Osteoporosis is a metabolic condition that leads to a reduction in bone density, resulting in weakened bones that are more brittle and prone to breaking. Osteogenesis imperfecta, also known as brittle bone disease, is a rare congenital genetic disorder characterized by extremely brittle bones. Sclerostin has been identified as a therapeutic target for both diseases.

In 2019, the US Food and Drug Administration (FDA) approved the use of the monoclonal antibody against sclerostin for the treatment of postmenopausal osteoporosis. Studies have also shown that the sclerostin antibody improves bone mass and bone strength in mice with osteogenesis imperfecta.

However, because sclerostin plays a protective role in the cardiovascular system, antibodies to sclerostin were found to increase the risk of heart attacks, strokes, and cardiovascular death during clinical trials. Therefore, the FDA requires a black box warning about possible cardiovascular risks. The research team strove to develop alternative drug options.

‘loop3’ identified as a new therapeutic target

Sclerostin suppresses bone formation by antagonizing the Wnt signaling pathway. The Wnt signaling pathway modulates stem cells responsible for skeletal tissue regeneration. Therefore, inhibition of sclerostin promotes bone growth.

The research team discovered that a loop3 domain in the central region of sclerostin can be used as a molecular target to inhibit sclerostin. Via genetic studies, it was shown that loop3 domain deficiency can inhibit the antagonistic effect of sclerostin against the Wnt signaling pathway, but does not affect the cardiovascular protective effect of sclerostin. The result suggests that the loop3 domain may serve as a molecular target to inhibit sclerostin while preserving its cardiovascular protective function.

The researchers then proceeded to examine aptamers that can specifically inhibit loop3 sclerostin. Aptamers are single-stranded DNA or RNA molecules that can selectively bind to molecular targets such as proteins. After binding to specific proteins, aptamers can inhibit protein-protein interactions and thus elicit certain therapeutic effects. Using combinatorial technology, an aptamer, aptscl56, was selected as a potential inhibitor of sclerostin targeting the loop3 structure.

Aptamer selected as an effective and safe sclerostin inhibitor

The research team examined the therapeutic functions of aptscl56 with osteoporosis rat models and osteogenesis imperfecta mouse models. They found that aptscl56 effectively promotes bone formation. On the other hand, the application of aptscl56 does not increase the risk of developing cardiovascular diseases such as aortic aneurysms and atherosclerotic development in both models.

The medical use of aptamers confers certain advantages, such as thermal stability and ease of synthesis. However, they are prone to rapid degradation and renal filtration. Therefore, the research team modified aptscl56 to produce an aptamer called Apc001 with a longer half-life. The team demonstrated that Apc001 promotes bone formation, increases bone mass, improves the integrity of bone microarchitecture, and improves bone mechanical properties in rats with osteoporosis and mice with osteogenesis imperfecta.

Clinical trials will begin in 2024

“The search for reliable and safe alternatives to overcome the limitations of currently available drugs is crucial to help patients in need of anabolic bone therapies. Our ongoing studies, ranging from the identification of molecular targets for sclerostin inhibition to the aptamer drug discoveryoffer hope for the development of next-generation sclerostin inhibitors in the near future,” said Professor Zhang Ge.

“Our search for alternative medicines for bone anabolic therapies is a good example of tripartite collaboration between academia, industry and government. The research work was carried out in part in collaboration with a local biotech company and was supported by the Innovation and Technology Fund. Some biotech companies on the mainland they were engaged in certain aspects of aptamer development research, such as toxicology testing. The collaborative efforts will continue to create more synergy and fruitful results,” said Professor Lyu Aiping.

the therapeutic aptamer The FDA granted Apc001 orphan drug designation for the treatment of imperfect osteogenesis in 2019.

More information:
Yuanyuan Yu et al, Targeting loop3 of sclerostin preserves its cardiovascular protective action and promotes bone formation, nature communications (2022). DOI: 10.1038/s41467-022-31997-8

Luyao Wang et al, Therapeutic aptamer targeting loop3 sclerostin to promote bone formation without increasing cardiovascular risk in mice with osteogenesis imperfecta, theranostics (2022). DOI: 10.7150/thno.63177

Citation: New Aptamer Drug for Bone Anabolic Therapies (December 19, 2022) Accessed December 19, 2022 at

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