Hereditary Hypophosphatemia is a series of disorders characterized by hypophosphatemic rickets with impaired phosphate reabsorption in the proximal renal tubules. X-linked hypophosphatemia (XLH, MIM 307800). XLH is caused by the loss-of-function mutation in the phosphate-regulating gene with homology to endopeptidase located on the X chromosome (PHEX) gene. Young XLH patients usually present with rickets, gait retardation, lower limb deformities, growth retardation, craniosynostosis and spontaneous dental abscesses. Adults with XLH experience diffuse musculoskeletal pain (bone and joints), early osteoarthritis, pseudo-fractures, enthesopathy, spinal stenosis, muscle weakness, and severe dental damage (Figure 1).

The long-acting sclerostin-loop3 nucleic acid aptamer Apc001OA for the treatment of XLH, developed by Prof. ZHANG Ge [Law Sau Fai Institute for Advancing Translational Medicine in Bone&Joint Diseases, Hong Kong Baptist University (HKBU)], Prof. ZHANG Zhenlin (Osteoporosis and Bone Diseases, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine) and Aptacure Therapeutics Ltd., was granted Orphan Drug Designation (DRU-2023-9894) and Pediatric Rare Disease Designation (RPD-2023-780) by the U.S. FDA on 22^ndFebruary, 2024, respectively.

Figure 1: Skeletal imaging of XLH patients at different times and different parts of the body

Prof. ZHANG Ge, leader of the project - director of TMBJ explains, "Genetic evidence shows that sclerostin deficiency significantly elevates serum phosphorus levels and increases bone mass in mice. Sclerostin is expected to be a potential therapeutic target for XLH. However, the marketed sclerostin antibody Romosozumab has caused serious cardiovascular and cerebrovascular events in phase III clinical trails, and the US-FDA has added a black box warning to the Romosozumab insert suggesting that it may increase the risk of heart attack, stroke, and cardiovascular disease, and has strictly limited its use to one year. We notably found that sclerostin could inhibit bone formation and protect the cardiovascular system via different structural domains (loops); identified that sclerostin loop3 contributed to the antagonistic effect of sclerostin on bone formation, while the protective effect of sclerostin on cardiovascular system was independent of sclerostin loop3 (Yu, Wang et al., Nat. Commun., 2022); and developed a nucleic acid aptamer Apc001 (Chinese Patent: ZL 2019 8 0012952.6) that specifically targets sclerostinloop3 (Wang, Yu et al. Theranostics,2022; Ni et al. ACS Appl Mater Interfaces, 2020; Yu et al. Acta Pharm Sin B, 2022). The long-acting dosage form of Apc001 (Apc001OA) promoted bone formation, increased bone mass and improved bone microarchitecture, and increase serum phosphate without cardiovascular concerns in Hyp mice (classic XLH mouse model).”

Prof. ZHANG Zhenlin, co-leader of the project - Director of the Osteoporosis and Bone Diseases, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, introduced: "XLH is one of the most common hereditary bone diseases, and more than 300 lines have been established in our center. Early testing of serum samples from patients with XLH showed that serum sclerostin levels were higher in XLH patients than in healthy controls (Chen et al. Dis Markers, 2022). The development of sclerostin loop3-specific aptamer with cardiovascular safety, bone-enhancing efficacy, and serum phosphorus-raising effects is expected to provide candidates for precision therapy targeting X-linked hypophosphatemic rickets patients with high serum sclerostin levels."

The study was funded by the Hong Kong Research Grants Council's Major Theme-based Research Scheme (T12-201/20-R), the Key Research and Development Program of the Ministry of Science and Technology of China (2018YFA0800800), the University-Industry Collaboration Programme of the Hong Kong Innovation and Technology Commission (UIM/298; UIM/328), and the Hong Kong Science and Technology Parks' Biomedical Incubation Programme for Start-ups (Aptacure), respectively .

The spokesperson of Aptacure Therapeutics Ltd. said, "The participating research team is currently conducting preclinical studies of the project, and the targeting of IND filing in China and the U.S. is being actively prepared, and the team is taking the opportunity of obtaining the U.S. FDA's Orphan Drug Designation and Pediatric Rare Disease Designation to apply the team's technical and professional strengths. team's technical and professional advantages to seek and create a safe and effective strategy for the treatment of X-linked hypophosphatemic rickets for the benefit of patients and society."

References

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