1. A novel therapeutic strategy for skeletal disorders: Proof of concept of gene therapy for X-linked hypophosphatemia
- Author
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Stéphane Hilliquin, N. Danièle, B. Baroukh, Severine Charles, Louisa Jauze, Fabienne Rajas, Lotfi Slimani, Agnès Linglart, Jérémy Sadoine, Claire Bardet, Giuseppe Ronzitti, Catherine Chaussain, Volha V. Zhukouskaya, Laetitia van Wittenberghe, Federico Mingozzi, Christian Leborgne, Généthon, Approches génétiques intégrées et nouvelles thérapies pour les maladies rares (INTEGRARE), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Généthon, Pathologies, imagerie et biothérapies oro-faciales = Orofacial pathologies, imaging and biotherapies (URP 2496), Université Paris Cité (UPCité), Signalisation Hormonale, Physiopathologie Endocrinienne et Métabolique, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Hôpital Bicêtre, Nutrition, diabète et cerveau (NUDICE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'Odontologie [Bretonneau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bretonneau, ANR-18-CE14-0018,HYPOSKEL,Hypophosphatémie liée à l'X : des mécanismes pathologiques de la minéralisation aux traitements des manifestations squelettiques(2018), Pathologies, Imagerie et Biothérapies oro-faciales (URP 2496), and Di Carlo, Marie-Ange
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Multidisciplinary ,business.industry ,viruses ,Genetic enhancement ,SciAdv r-articles ,Diseases and Disorders ,Gene transfer ,Bioinformatics ,X-linked hypophosphatemia ,medicine.disease ,Virus ,stomatognathic diseases ,Text mining ,Refractory ,Proof of concept ,Medicine ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,[SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Biomedicine and Life Sciences ,Health and Medicine ,business ,General Economics, Econometrics and Finance ,Research Article ,Therapeutic strategy - Abstract
Description, A new therapeutic approach for the treatment of a skeletal disorder with AAVs bypasses bone resistance to gene transfer., 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.
- Published
- 2021
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