A research team led by Baptist University discovered a molecular target for osteogenesis therapy and developed the corresponding aptamer drug as a sclerostin inhibitor.
Osteostatin is a protein that inhibits bone formation.
Compared with antibody drugs known to increase the risk of cardiovascular disease, the discovery brings hope for the development of effective next-generation treatments for osteoporosis and osteogenesis imperfecta.
The new drug is currently in the pre-clinical development stage, and the research team plans to start clinical trials in the United States and the Mainland in 2024.
HKBU scholars participating in the research (from left) Yu Yuanyuan, Prof. Lu Aiping, Prof. Zhang Ge, and postdoctoral researcher Wang Luyao present their new research findings.
(Provided by HKBU)
Osteoporosis is a metabolic disease that causes bone density and strength to decrease, making bones weaker and more likely to break.
Osteogenesis imperfecta, also known as "brittle bones" or "glass bone", is a rare congenital genetic disease characterized by extremely fragile bones.
Osteostatin, a protein that inhibits bone formation, has been identified as a therapeutic target for osteoporosis and osteogenesis imperfecta.
In 2019, the US Food and Drug Administration (FDA) approved the use of monoclonal antibodies that inhibit sclerostestatin for the treatment of postmenopausal osteoporosis.
Studies have shown that monoclonal antibodies can increase bone weight and strength in mice with osteogenesis imperfecta.
However, osteostatin has the effect of protecting the cardiovascular system. In clinical trials, monoclonal antibody drugs have increased the risk of heart attack, stroke and death from cardiovascular disease. Therefore, the FDA requires the drug to be marked with a black box warning of cardiovascular risk.
Lu Aiping, Director of HKBU Institute of Integrative Bioinformatics Medicine and Translational Science, Zhang Ge, Director of HKBU Law Shouhui Institute of Translational Medicine for Bone and Joint Diseases, and Manager of HKBU Guangdong-Hong Kong-Macao Greater Bay Area Aptamer Translational Medicine and Drug Discovery International Cooperation Platform and Yu Yuanyuan, Assistant Professor of the School of Chinese Medicine at HKBU, leads a research team dedicated to developing alternative medicines and providing new options for patients.
Osteoporosis is a metabolic disease that causes loss of bone density and strength.
(File photo/photo by Yu Junliang)
The research team found that the "loop3 domain" located in the core region of osteostatin can become a molecular target for the inhibition of osteostatin.
Through genetic research methods, the researchers found that when osteostatin loses the loop3 domain, the antagonism of the Wnt signaling pathway will be inhibited, but its cardiovascular protection will not be affected, which means that the loop3 domain can be used as an inhibitor of osteostatin molecular target of sclerostestatin while retaining the cardiovascular protective function of sclerostestatin.
The researchers then screened for aptamers that specifically inhibited sclerostostatin loop3.
Aptamers are single-stranded DNA or ribonucleic acid molecules that can selectively bind to molecular targets such as proteins.
After the aptamer binds to a specific protein, it can inhibit the interaction between proteins, so as to achieve certain therapeutic effects.
They used combinatorial technology to screen out the aptamer "aptscl56" as a potential inhibitor of osteostatin targeting the loop3 structure.
Bone is one of the health problems of modern people.
(File photo/Photo by Huang Baoying)
The research team tested the therapeutic efficacy of aptscl56 in a rat model of postmenopausal osteoporosis and a mouse model of osteogenesis imperfecta, and found that it was effective in promoting bone formation in both models.
On the other hand, the use of aptscl56 did not increase the risk of cardiovascular diseases, such as aortic aneurysm and atherosclerosis, in rats and mice.
The use of aptamer drugs in medicine has certain advantages, such as stability to temperature and ease of synthesis.
However, they are easily and rapidly degraded and filtered by the kidneys.
The research team then made some adjustments to the chemical properties of aptscl56 to create an aptamer "Apc001" with a longer half-life.
The team demonstrated that Apc001 can promote bone formation in rats with osteoporosis and mice with osteogenesis imperfecta, increase bone weight, improve the integrity of bone microstructure, and improve bone mobility.
Clinical trials planned for 2024
Professor Zhang Ge said that finding reliable and safe alternatives to address the limitations of existing drugs is critical to helping patients who need osteogenic therapy.
He pointed out that from the search for molecular targets for the inhibition of osteostatin to the discovery of aptamer drugs, he believed that a new generation of osteostatin inhibitors could be developed in the near future.
The aptamer Apc001 has received orphan drug designation from the US Food and Drug Administration in 2019 for the treatment of osteogenesis imperfecta.
Relevant research results have been published in international academic journals Nature Communications and Theranostics.
The new drug is currently in the pre-clinical development stage, and the research team plans to start clinical trials in the United States and the Mainland in 2024.
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