ESPEYB19 14. Science and Medicine New treatments (2 abstracts)
14.14. A novel therapeutic strategy for skeletal disorders: Proof of concept of gene therapy for X-linked hypophosphatemia
Volha V Zhukouskaya , Louisa Jauze , Séverine Charles , Christian Leborgne , Stéphane Hilliquin , Jérémy Sadoine , Lotfi Slimani , Brigitte Baroukh , Laetitia van Wittenberghe , Natalie Danièle , Fabienne Rajas , Agnès Linglart , Federico Mingozzi , Catherine Chaussain , Claire Bardet & Giuseppe Ronzitti
Science Advances, 2021,7:eabj5018 doi: 10.1126/sciadv.abj5018
Brief Summary: The authors developed a liver-targeting adeno-associated virus (AAV) vector carrying C-terminal FGF23 (cFGF23) to inhibit FGF23 signalling in a mouse model for X-linked hypophosphataemic rickets (hyp-duk mice). They were able to show that a single injection of AAV cFGF23 rescued the hyp-duk phenotype.
X-linked hypophosphataemic rickets (XLH) is the most common form of rickets associated with elevated FGF23. Mutations in the PHEX-gene, encoding a metalloprotease, lead to high circulating FGF23 concentrations resulting in increased renal phosphate waste and impaired 1,25(OH)2-vitamin D production. FGF23 acts by binding to the FGF23 receptor and its co-receptor Klotho. cFGF23 competes for the binding to the FGF23-receptor/Klotho-complex blocking native FGF23 action.
This paper, using a mouse model for XLH (hyp-duk mice), describes a series of comprehensive experiments that are presented and analysed in detail. The experiments showed that a single injection of AAV cFGF23 resulted in efficient liver targeting. Only those animals that had received an AAV vector expressing cFGF23co-albumin showed increased blood phosphate levels, suggesting that cFGF23 alone is unstable. One injection of AAV cFGF23 restored the expression of the Npt2a transporter mRNA in the kidney. However, the normalization of blood phosphate levels was only transitory: after 3 months the blood phosphate level of treated mice was similar to controls. This could be explained either by phosphate reallocation to bone or by increased expression of Nat2b in the kidney. Interestingly, in contrast to treatment with the monoclonal human FGF23 antibody Burosumab, treatment with AAV cFGF23 did not affect the expression of the key enzymes involved in vitamin D metabolism nor did it affect circulating 1,25(OH)2-vitamin D levels. However, blood calcium rose to normal values in treated animals. Finally, the osteoarticular phenotype and partially bone length were restored in treated mice. Consequently, linear growth improved significantly in treated animals.
This study adds to present knowledge the proof of concept of the efficacy of liver-targeted gene therapy in a mouse model for XLH. Furthermore, in this XLH mouse model FGF23 regulation of vitamin D activation was unaffected. Nevertheless, blood calcium levels normalized in treated mice, suggesting a selective effect of cFGF23 on calcium regulation. Further work will be necessary to elucidate the molecular mechanism for this effect.
Volume 19
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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