ESPE2021 ePoster Category 1 Bone B (10 abstracts)
AAV liver gene therapy-mediated inhibition of FGF23 signaling as a therapeutic strategy for X-linked hypophosphatemia
Volha Zhukouskaya 1,2 , Louisa Jauze 1,2,3 , Séverine Charles 2,1 , Christian Leborgne 2,1 , Stéphane Hilliquin 4 , Jérémy Sadoine 5 , Lotfi Slimani 5 , Brigitte Baroukh 5 , Laetitia van Wittenberghe 2 , Natalie Daniele 2 , Fabienne Rajas 3 , Agnès Linglart 6,7 , Federico Mingozzi 1,2 , Catherine Chaussain 5,8,9 , Claire Bardet 5 & Giuseppe Ronzitti 2,1
1Université Paris-Saclay, Univ Evry, Inserm, Integrare Research Unit UMR_S951, Evry, France; 2Genethon, Evry, France; 3Institut National de la Santé et de la Recherche Médicale, U1213, Lyon, France; 4Department of Rheumatology, Cochin Hospital, Université de Paris, Paris, France; 5Université de Paris, Laboratory Orofacial Pathologies, Imaging and Biotherapies URP2496 and FHU-DDS-Net, Dental School, and Plateforme d’Imagerie du Vivant (PIV), Montrouge, France; 6AP-HP, Department of Endocrinology and Diabetology for Children and Department of Adolescent Medicine, Bicêtre Paris-Saclay Hospital, Le Kremlin-Bicêtre, France; 7Paris Saclay University, Faculté de Médecine, Le Kremlin-Bicêtre, France; 8AP-HP, Department of Odontology-Rare Disorders, Hospital Bretonneau, and UR2496 Université de Paris, Paris, France; 9Université de Paris, 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.
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