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Endocrine Abstracts (2021) 73 OC6.2 | DOI: 10.1530/endoabs.73.OC6.2

1Genethon, Université Paris-Saclay, Univ Evry, Inserm, Integrare research unit UMR_S951, Evry, France; 2Université de Paris, Laboratory Orofacial Pathologies, Imaging and Biotherapies URP2496 and FHU-DDS-Net, Dental School, and Plateforme d’Imagerie du Vivant (PIV), Montrouge, France; 3Institut National de la Santé et de la Recherche Médicale, U1213, Lyon, F-69008, Lyon, France; 4Department of Rheumatology, Cochin Hospital, Université de Paris, Paris, France; 5Genethon, Evry, France; 6Paris Saclay University, Faculté de Médecine, Le Kremlin-Bicêtre, France; 7AP-HP, Department of Endocrinology and Diabetology for children and Department of Adolescent Medicine, Bicêtre Paris-Saclay Hospital, Le Kremlin-Bicêtre, France; 8AP-HP, Department of Odontology-Rare disorders, Hospital Bretonneau, and UR2496 Université de Paris, France

Adeno‐associated virus (AAV) gene therapy reached the maturity and a liver-targeting approach is currently used as a replacement treatment for rare hepatic and muscular diseases. X-linked hypophosphatemia (XLH) is a rare disease associated with hyperfunction of fibroblast growth factor 23 (FGF23) in bone and characterized by severe skeletal deformities and short stature. The current medical therapies for XLH requires life-long repeated treatment presenting major limitations as an inadequate treatment compliance due to i) multiple doses per day and severe long-term side effects for the conventional treatment (based on phosphate supplementation and active vitamin D analogs) or ii) an extremely expensive cost for the health care system for the monoclonal anti-FGF23 antibody therapeutic. Here we studied the hypothesis whether the liver-targeting approach could be used as a therapeutic modality for rare diseases associated with hyperfunction of growth factors as XLH, treating this bone pathology with a single injection. We elaborated a novel therapeutic approach for XLH based on a single injection of AAV gene therapy aiming to stimulate the production of a FGF23 neutralizing factor (cFGF23) in the liver in a murine model of XLH, the Hyp-Duk mouse. We demonstrated that one single injection of AAV-cFGF23 treatment led to restoration of impaired skeletal phenotype, and to significant reduction of osteomalacia, bone and joint alterations in Hyp-Duk mice. This provides a proof-of-concept that the liver-targeting approach represents an adequate modality to rescue the growth factor’s hyperfunction, thus opening the new perspectives on the treatment of skeletal diseases by gene therapy.

Volume 73

European Congress of Endocrinology 2021

22 May 2021 - 26 May 2021

European Society of Endocrinology 

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