Treatment and prediction of therapeutic responses in patients suffering from Friedreich ataxia

US11857532B2 · kind B2 · utility

Assignees

• INSERM (INSTITUT NATIONAL DE LA SANTÉ ET DE LA RECHERCHE MÉDICALE) · FR
• Moraine Corporation · FR
• ASSISTANCE PUBLIQUE—HÔPITAUX DE PARIS (APHP) · FR

Inventors

• Anne Agnès Rötig · Paris, FR
• Arnold Munnich · Paris, FR
• Floriane Petit · Paris, FR

Key dates

• Filing date: Dec 27, 2019
• Grant date: Jan 2, 2024
• Expiry date: Jul 11, 2040

Classification

• Technology area (CPC A): Human Necessities
• CPC primary: A61P25/28
• WIPO field: Pharmaceuticals
• WIPO sector: Chemistry

Abstract

Friedreich ataxia (FRDA) is caused by a GAA repeat expansion in FXN gene that encodes a mitochondrial protein, frataxin, involved in iron sulfur complex (ISC) assembly. Frataxin deficiency results in abnormal ISC containing proteins, namely respiratory chain complex I-III and aconitases and accumulation of iron in brain and heart of patients. Here, the inventors show that FRDA fibroblasts are unable to limit iron uptake inducing a massive cytosolic iron accumulation and to a lesser extent in mitochondria. The inventors also observed increased transferrin receptor (TfR1) steady state levels and membrane TfR1 accumulation that they ascribed to impaired post-translational modification by palmitoylation as well as delayed transferrin recycling. Finally, the inventors showed that artesunate, dichloroacetate and Coenzyme-A improved TfR1 palmitoylation and thus represent candidate molecules for the treatment of patients with Friedreich ataxia. Thus the present invention relates to methods of treating Friedreich ataxia (FRDA) as well as to methods of predicting whether a patient suffering from FRDA will achieve a therapeutic response.