Osteogenesis imperfecta, also known as brittle bone disease (Figure 1), is a rare genetic bone disorder. Children with this condition experience severe fractures from minor impacts and are often referred to as "glass dolls." Currently, there is a lack of specialized drugs for the treatment of osteogenesis imperfecta in clinical practice. The US FDA refers to the development of drugs for such diseases as "orphan drugs." Chinese drug regulatory authorities have also included these diseases in the list of rare diseases. Obtaining orphan drug designation from the US FDA will bring a series of benefits for subsequent drug development, including reducing the sample size required for clinical trials, potentially accelerating the review process, exempting new drug application fees, and gaining market exclusivity for seven years after approval (Figure 2).

Figure 1 The differences in bone between healthy individuals and patients with osteogenesis imperfecta.

Nore：Image from Joan C. Marini, et al. Osteogenesis imperfecta. Nature Reviews 3: 17052-17072 and《Don't blindly correct your baby's frog legs》

Figure 2 A timeline chart of FDA and ODD application times and policy incentives.

Note：The picture comes from the WeChat public account of "Yinquan Pharmaceutical Administration".

Professor Zhang Ge, Associate Director of the Law Sau Fai Institute for Advancing Translational Medicine in Bone & Joint Diseases (TMBJ) at Hong Kong Baptist University（TMBJ：http://tmbj.hkbu.edu.hk/）, and Professor Lyu Aiping, from the Institute of Biomedical and Translational Sciences (IBTS) at Hong Kong Baptist University（IBTS：http://ibts.hkbu.edu.hk/）, have discovered a novel aptamer targeting Sclerostin. This aptamer obtained orphan drug designation (ODD) from the U.S. Food and Drug Administration (FDA) on August 19, 2019, for the treatment of osteogenesis imperfecta (DRU-2019-6966).

Professor Zhang Ge, the project planner from the Law Sau Fai Institute for Advancing Translational Medicine in Bone & Joint Diseases (TMBJ) at Hong Kong Baptist University（TMBJ：http://tmbj.hkbu.edu.hk/）stated, "Genetic evidence suggests that inhibiting the Sclerostin can improve the phenotype of osteogenesis imperfecta. However, clinical evidence indicates that monoclonal antibodies targeting the Sclerostin still carry significant and unavoidable cardiovascular risks. Our basic research has discovered that the Sclerostin can participate in inhibiting bone formation and protecting the cardiovascular system through different structural domains. This led us to strategically screen and optimize the synthesis of a new class of molecules, known as anti-Sclerostin aptamers. It is anticipated that these aptamers not only significantly promote the improvement of the osteogenesis imperfecta phenotype but also do not affect the cardiovascular protective effects of the Sclerostin, thereby avoiding increased cardiovascular risks."

Prof. Lyu Aiping, Director of the Institute of Biomedical and Translational Sciences (IBTS) at Hong Kong Baptist University, and co-planner of the project, explained, "Traditional aptamer screening involves searching for suitable molecules from a DNA library of over 10^15 candidates, akin to finding a needle in a haystack. However, in the screening of the Sclerostin aptamer, we applied artificial intelligence technology to high-throughput screening. This not only reduces manpower, shortens screening time, and minimizes reagent usage but, more importantly, enables systematic analysis of candidate molecules using artificial intelligence. This allows for the rapid identification of suitable molecules from a vast candidate library, thereby avoiding the potential omission of high-quality candidates in traditional analysis methods."

Prof. Yu Yuanyuan, Director of the Cell and Molecular Biology Laboratory at the International Research Platform for Aptamer-based Translational Medicine and Drug Discovery in the Greater Bay Area (https://www.hkaptamer.com/), a participant in the project, stated, "Aptamers are artificially synthesized single-stranded oligonucleotides (DNA or RNA) or oligopeptides. They exert their biological functions through high-affinity and highly specific binding to target substances via three-dimensional structural complementarity. Aptamers function similarly to antibodies but offer several advantages, including better chemical stability, improved batch-to-batch reproducibility, and lower immunogenicity. Aptamers can be selected, amplified, and enriched through the systematic evolution of ligands via exponential enrichment (SELEX) technique, thereby achieving superior screening efficiency. Depending on the requirements of different targets, aptamer screening can be customized. For example, by setting up positive and negative screening processes, candidate molecules that specifically bind to the positive screening target can be strategically obtained while simultaneously eliminating candidate molecules that may cause adverse reactions by binding to the negative screening target. In the screening of the Sclerostin aptamer, we tailored the selection process according to the different functional domains of the Sclerostin, resulting in the identification of aptamers that not only promote the improvement of osteogenesis imperfecta phenotype but also do not affect the cardiovascular system."

Dr. Ni Shuaijian, Director of the Chemical Synthesis Laboratory at the International Research Platform for Aptamer-based Translational Medicine and Drug Discovery in the Greater Bay Area (https://www.hkaptamer.com/), a participant in the project, explained, "Nucleic acid aptamers obtained through SELEX principles are composed of natural bases, which typically exhibit poor stability in the body due to enzymatic degradation. Additionally, their relatively small molecular weight makes them susceptible to renal clearance. Therefore, chemical modifications are necessary to enhance their in vivo stability and pharmacokinetic properties. Solid-phase synthesis provides a convenient method for chemically modifying nucleic acid aptamers. We have prepared chemically modified Sclerostin nucleic acid aptamers using solid-phase synthesis technology."

Prof. Ren Kangning, Vice Director of the International Research Platform for Aptamer-based Translational Medicine and Drug Discovery in the Greater Bay Area (https://www.hkaptamer.com/) and Director of the Microfluidics Laboratory, added, "For this screening, we applied a microfluidic system designed by our platform. Microfluidics is a technology that precisely controls and manipulates fluids at the microscale, particularly in submicron structures. By applying microfluidics to aptamer screening, we can exponentially increase the screening efficiency, significantly improve reproducibility, and enhance the success rate."

Prof. Zhang zhenlin, Chairman of the Osteoporosis and Mineral Metabolism Diseases Branch of the Chinese Medical Association, Chief of the Osteoporosis Department at Shanghai Sixth People's Hospital affiliated with Shanghai Jiao Tong University, and a renowned authority in bone metabolism and bone diseases in China, stated, "In 2019, the Osteoporosis and Mineral Metabolism Diseases Branch of the Chinese Medical Association issued clinical guidelines for osteogenesis imperfecta in China. The new molecule discovered by Professor Zhang Ge and Professor Lv Aiping from Hong Kong Baptist University has obtained orphan drug designation from the US FDA, which is of great significance for promoting the development of orphan drugs for osteogenesis imperfecta in China. It will also further promote collaboration between Shanghai and Hong Kong in the research and development of innovative drugs for osteogenesis imperfecta in China."

Prof. Chen Lin, Chief Scientist of the National Key Research and Development Program "Effects and Mechanisms of Genetic Calcium and Phosphorus Metabolic Disorders on the Development of Children's Skeleton and Organs," Head of the Basic and Translational Medicine Group of the Osteoporosis and Mineral Metabolism Diseases Branch of the Chinese Medical Association, and Professor at the Third Military Medical University, explained, "Basic research and the translational development of rare diseases, including mineral metabolism disorders, have attracted increasing attention from the Ministry of Science and Technology. In 2018, the National Key Research and Development Program's major project on 'Developmental Programming and Metabolic Regulation' allocated a considerable amount of research funds to this specific field. As part of the cross-strait innovation system, Hong Kong, and Professor Zhang Ge's team from Hong Kong Baptist University, were invited to join this research program and apply nucleic acid aptamer technology to the basic and translational research of genetic calcium and phosphorus metabolic disorders in children."

A spokesperson from Aptacure Therapeutics Ltd. stated, "The research team involved in this project is currently conducting preclinical studies, and preparations for IND (Investigational New Drug) application are actively underway. Taking the opportunity of obtaining orphan drug designation from the US FDA, the team is utilizing their technical advantages to seek and develop effective treatment strategies for osteogenesis imperfecta, benefiting patients and society."