Graphic 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 bone anabolic therapies using a selected aptamer that serves as an inhibitor of sclerostin, a protein that prevents bone growth. This discovery gives hope for the development of an effective next-generation treatment against osteoporosis and osteogenesis imperfecta, without cardiovascular risk compared to the marketed antibody drug.
Research results have been published in journals Nature Communication and Theranostics. The new drug is in the development stage of pre-clinical trials, and the research team expects to begin clinical trials in the United States and on the mainland in 2024.
Current drugs increase cardiovascular risk
Osteoporosis is a metabolic disease that causes a reduction in bone density, resulting in weakened bones that are more fragile and susceptible to breakage. Osteogenesis imperfecta, also known as brittle bone disease, is a rare congenital genetic disorder characterized by extremely fragile bones. Sclerostin has been identified as a therapeutic target for both diseases.
In 2019, the United States 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, the sclerostin antibody has been found to increase the risk of heart attack, stroke, and cardiovascular death in clinical trials. Therefore, a black box warning for potential cardiovascular risks is required by the FDA. The research team worked hard to develop drug alternatives.
‘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. Through genetic studies, it has been shown that loop3 domain deficiency can inhibit the antagonistic effect of sclerostin against the Wnt signaling pathway, but it 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 screen for aptamers capable of specifically inhibiting the sclerostin3 loop. Aptamers are single-stranded DNA or RNA molecules that can selectively bind to molecular targets such as proteins. After binding with specific proteins, aptamers can inhibit protein-protein interactions and thus cause certain therapeutic effects. Using combinatorial technology, an aptamer, aptscl56, was selected as a potential sclerostin inhibitor targeting the loop3 structure.
Aptamer selected as an effective and safe sclerostin inhibitor
The research team examined the therapeutic functions of aptscl56 with osteoporotic 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 subject 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 the integrity of bone microarchitecture and improves bone mechanical properties in rats with osteoporosis and mice with osteogenesis imperfecta.
Clinical trials to start in 2024
“The search for reliable and safe alternatives to overcome the limitations of currently available drugs is crucial to help patients who need bone-anabolic therapies. Our ongoing studies, which range from the identification of molecular targets for sclerostin inhibition to the discovery of aptamer drugs, offer hope for the development of next-generation sclerostin inhibitors in the near future,” said Professor Zhang Ge.
“Our search for alternative drugs for bone anabolic therapies is a good example of three-way collaboration between academia, industry and government. The research work was partly conducted in collaboration with a local biotechnology company, and they were supported by the Innovation and Technology Fund.Some biotechnology companies on the continent were engaged in some aspects of developmental research for the aptamer, such as toxicology testing.The collaborative efforts will continue to create more synergy and fruitful results,” said Professor Lyu Aiping.
The therapeutic aptamer Apc001 received orphan drug designation from the FDA for the treatment of osteogenesis imperfecta in 2019.
Yuanyuan Yu et al, Targeting loop3 of sclerostin preserves its cardiovascular protective action and promotes bone formation, Nature Communication (2022). DOI: 10.1038/s41467-022-31997-8
Luyao Wang et al, Therapeutic aptamer targeting the sclerostin3 loop to promote bone formation without increasing cardiovascular risk in mice with osteogenesis imperfecta, Theranostics (2022). DOI: 10.7150/thno.63177
Provided by Hong Kong Baptist University
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