The AAV-based therapy targets the liver’s hepatocytes to express therapeutic proteins for secretion into the bloodstream and long-lasting treatment of the rare disease.
PARIS, FRANCE (November, 2021) – Genethon, a unique non-profit gene therapy R&D organization founded by the French Muscular Dystrophy Association (AFM-Telethon), announced today publication in the open-access journal Science Advances of research describing advances in using AAV-based gene therapy for potential long-lasting treatment of X-linked hypophosphatemia (XLH), a serious skeletal disease caused by low levels of phosphate (“A novel therapeutic strategy for skeletal disorders: Proof of concept of gene therapy for X-linked hypophosphatemia,”). The study results from a collaboration between Genethon and the Laboratory of Orofacial Pathologies, Université de Paris led by Claire Bardet and Catherine Chaussain.
“Our research demonstrates that AAV gene therapy can harness the liver as a biofactory to express soluble factors capable to act on distant organs. This approach, here used to correct XLH, can potentially be applied also to other rare life-threatening, inherited diseases,” said Giuseppe Ronzitti, Head of the Immunology and liver gene transfer team at Genethon and last author of the article.
XLH is a skeletal disorder characterized by the increased production of fibroblast growth factor 23 (FGF23), which reduces the amount of phosphate in the blood causing skeletal deformities, bone pain, short stature, and severe dental abscesses.
The standard of care combines oral administration of phosphate with an active form of vitamin D, partially improving the quality of life. However, this strategy can cause serious side effects. Recently, a monoclonal antibody to inhibit production of FGF23 has been approved for XLH, but it is an expensive, lifelong treatment.
The Genethon researchers used AAV vectors to deliver into the livers of XLH mouse models a gene encoding for an engineered form of FGF23. When secreted into the bloodstream, the modified FGF23 is designed to interfere with the over-production of FGF23 and offset the reduction in blood phosphate.
The study showed that gene therapy corrected skeletal damage caused by XLH in the mice and established proof of concept for clinical development of the treatment.
The researchers concluded, “Our results also support the use of the liver as a platform to secrete factors able to modulate pathways in tissues refractory to AAV gene therapy, such as bone or kidney, further expanding the therapeutic potential of the approach.”