A novel therapeutic strategy for skeletal disorders: Proof of concept of gene therapy for X-linked hypophosphatemia.

Autor:	Zhukouskaya VV; Genethon, 91000 Evry, France.; Université Paris-Saclay, Univ Evry, Inserm, Genethon, INTEGRARE Research Unit UMR_S951, 91000 Evry, France.; Université de Paris, Institut des maladies musculo-squelettiques, Laboratory Orofacial Pathologies, Imaging and Biotherapies URP2496 and FHU-DDS-Net, Dental School, and Plateforme d'Imagerie du Vivant (PIV), Montrouge, France.; Paris-Saclay University, INSERM U1185, AP-HP, DMU SEA, Endocrinology and Diabetes for Children, Reference Center for Rare Diseases of the Calcium and Phosphate Metabolism, OSCAR filière, EndoRare, and BOND ERN, Bicêtre Hospital, Le Kremlin-Bicêtre, France., Jauze L; Genethon, 91000 Evry, France.; Université Paris-Saclay, Univ Evry, Inserm, Genethon, INTEGRARE Research Unit UMR_S951, 91000 Evry, France.; Institut National de la Santé et de la Recherche Médicale, U1213, Lyon F-69008, France., Charles S; Genethon, 91000 Evry, France.; Université Paris-Saclay, Univ Evry, Inserm, Genethon, INTEGRARE Research Unit UMR_S951, 91000 Evry, France., Leborgne C; Genethon, 91000 Evry, France.; Université Paris-Saclay, Univ Evry, Inserm, Genethon, INTEGRARE Research Unit UMR_S951, 91000 Evry, France., Hilliquin S; Université de Paris, Institut des maladies musculo-squelettiques, Laboratory Orofacial Pathologies, Imaging and Biotherapies URP2496 and FHU-DDS-Net, Dental School, and Plateforme d'Imagerie du Vivant (PIV), Montrouge, France.; AP-HP, Department of Rheumatology, Cochin Hospital, Université de Paris, Paris, France., Sadoine J; Université de Paris, Institut des maladies musculo-squelettiques, Laboratory Orofacial Pathologies, Imaging and Biotherapies URP2496 and FHU-DDS-Net, Dental School, and Plateforme d'Imagerie du Vivant (PIV), Montrouge, France., Slimani L; Université de Paris, Institut des maladies musculo-squelettiques, Laboratory Orofacial Pathologies, Imaging and Biotherapies URP2496 and FHU-DDS-Net, Dental School, and Plateforme d'Imagerie du Vivant (PIV), Montrouge, France., Baroukh B; Université de Paris, Institut des maladies musculo-squelettiques, Laboratory Orofacial Pathologies, Imaging and Biotherapies URP2496 and FHU-DDS-Net, Dental School, and Plateforme d'Imagerie du Vivant (PIV), Montrouge, France., van Wittenberghe L; Genethon, 91000 Evry, France., Danièle N; Genethon, 91000 Evry, France., Rajas F; Institut National de la Santé et de la Recherche Médicale, U1213, Lyon F-69008, France., Linglart A; Paris-Saclay University, INSERM U1185, AP-HP, DMU SEA, Endocrinology and Diabetes for Children, Reference Center for Rare Diseases of the Calcium and Phosphate Metabolism, OSCAR filière, EndoRare, and BOND ERN, Bicêtre Hospital, Le Kremlin-Bicêtre, France., Mingozzi F; Genethon, 91000 Evry, France.; Université Paris-Saclay, Univ Evry, Inserm, Genethon, INTEGRARE Research Unit UMR_S951, 91000 Evry, France., Chaussain C; Université de Paris, Institut des maladies musculo-squelettiques, Laboratory Orofacial Pathologies, Imaging and Biotherapies URP2496 and FHU-DDS-Net, Dental School, and Plateforme d'Imagerie du Vivant (PIV), Montrouge, France.; Paris-Saclay University, INSERM U1185, AP-HP, DMU SEA, Endocrinology and Diabetes for Children, Reference Center for Rare Diseases of the Calcium and Phosphate Metabolism, OSCAR filière, EndoRare, and BOND ERN, Bicêtre Hospital, Le Kremlin-Bicêtre, France.; AP-HP, Reference Center for Rare Disorders of the Calcium and Phosphate Metabolism, Dental Medicine Department, Bretonneau Hospital, GHN-Université de Paris, Paris 75018, France., Bardet C; Université de Paris, Institut des maladies musculo-squelettiques, Laboratory Orofacial Pathologies, Imaging and Biotherapies URP2496 and FHU-DDS-Net, Dental School, and Plateforme d'Imagerie du Vivant (PIV), Montrouge, France., Ronzitti G; Genethon, 91000 Evry, France.; Université Paris-Saclay, Univ Evry, Inserm, Genethon, INTEGRARE Research Unit UMR_S951, 91000 Evry, France.
Jazyk:	angličtina
Zdroj:	Science advances [Sci Adv] 2021 Oct 29; Vol. 7 (44), pp. eabj5018. Date of Electronic Publication: 2021 Oct 27.
DOI:	10.1126/sciadv.abj5018
Abstrakt:	Adeno-associated virus (AAV) vectors are a well-established gene transfer approach for rare genetic diseases. Nonetheless, some tissues, such as bone, remain refractory to AAV. X-linked hypophosphatemia (XLH) is a rare skeletal disorder associated with increased levels of fibroblast growth factor 23 (FGF23), resulting in skeletal deformities and short stature. The conventional treatment for XLH, lifelong phosphate and active vitamin D analogs supplementation, partially improves quality of life and is associated with severe long-term side effects. Recently, a monoclonal antibody against FGF23 has been approved for XLH but remains a high-cost lifelong therapy. We developed a liver-targeting AAV vector to inhibit FGF23 signaling. We showed that hepatic expression of the C-terminal tail of FGF23 corrected skeletal manifestations and osteomalacia in a XLH mouse model. Our data provide proof of concept for AAV gene transfer to treat XLH, a prototypical bone disease, further expanding the use of this modality to treat skeletal disorders.
Databáze:	MEDLINE
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