19 Dec 2022
Osteoporosis is a metabolic condition which leads to a reduction in bone density, resulting in weakened bones that are more fragile and likely to break. Osteogenesis imperfecta, also known as “brittle bone disease”, is a rare congenital genetic disorder characterised by extremely fragile bones. For both diseases, sclerostin has been identified as a therapeutic target.
Sclerostin is a protein that prevents bone growth by antagonising the “Wnt signalling pathway”, which modulates the stem cells responsible for skeletal tissue regeneration. At the same time, it plays a protective role in the cardiovascular system.
In 2019, the US Food and Drug Administration (FDA) approved the use of the monoclonal antibody against sclerostin to treat postmenopausal osteoporosis. However, it was seen that the sclerostin antibody increased the risk of heart attacks, stroke and cardiovascular death during clinical trials.
A research team led by HKBU has identified a molecular target for bone anabolic therapies using a selected aptamer that serves as an inhibitor of sclerostin, offering hope for the development of an effective next-generation treatment for osteoporosis and osteogenesis imperfecta. The research findings have been published in the international academic journals Nature Communications and Theranostics.
The research team was led by Professor Lyu Aiping, Dr. Kennedy Y.H. Wong Endowed Professor in Chinese Medicine and Director of the Institute of Integrated Bioinformedicine and Translational Science; Professor Zhang Ge, Director of the Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases; and Dr Yu Yuanyuan, Manager of the Guangdong-Hong Kong-Macau Greater Bay Area International Research Platform for Aptamer-based Translational Medicine and Drug Discovery and Assistant Professor of the School of Chinese Medicine.
“loop3” identified as a new therapeutic target
The research team discovered through genetic studies that the deficiency of the “loop3 domain” in the core region of sclerostin can inhibit sclerostin’s antagonistic effect against the Wnt signalling pathway without affecting the cardiovascular protective effect of sclerostin. The result suggests that the loop3 domain can serve as a molecular target for inhibiting sclerostin while preserving its cardiovascular protective function.
The researchers then proceeded to screen aptamers that can specifically inhibit sclerostin loop3. Aptamers are single-stranded DNA or RNA molecules that can selectively bind to molecular targets and inhibit protein–protein interactions. Through a combinatorial technology, an aptamer “aptscl56” was selected as a potential sclerostin inhibitor that targets the loop3 structure.
Aptamer selected as effective and safe sclerostin inhibitor
The research team examined aptscl56’s therapeutic functions with osteoporotic rat models and osteogenesis imperfecta mouse models. They found that aptscl56 effectively promote 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.
While the medical use of aptamers confers certain advantages, such as thermal stability and ease of synthesis, they are prone to rapid degradation and renal filtration. The research team therefore modified aptscl56 to produce an aptamer named “Apc001” with a longer half-life. The team demonstrated that Apc001 promotes bone formation, increases bone mass, improves bone microarchitecture integrity, and enhances bone mechanical properties in rats with osteoporosis and mice with osteogenesis imperfecta.
The therapeutic aptamer Apc001 was granted orphan drug designation by the FDA for the treatment of osteogenesis imperfecta in 2019. The new drug is at the pre-clinical trial development stage, and the research team plans to start clinical trials in the US and on the Mainland in 2024.
“Our search for alternative drugs for bone anabolic therapies is a good example of tripartite collaboration between academia, industry and the government. The research work was partly conducted in collaboration with a local biotechnology company, and it was supported by the Innovation and Technology Fund. Some biotechnology companies in the Mainland were engaged in certain aspects of developmental research for the aptamer, such as toxicology tests. The collaborative efforts will continue to create more synergy and fruitful results,” says Professor Lyu Aiping.