CureMILS – A reprogramming-based strategy for drug repositioning in patients with mitochondrial DNA-associated Leigh syndrome

CureMILS is an innovative research project funded by the E-Rare ERA-Net with a budget of €2.4 million (2021–2024), coordinated by Prof. Alessandro Prigione (Heinrich Heine University), with Dr. Emanuela Bottani serving as Early Career Principal Investigator.  

Mitochondrial DNA (mtDNA)-associated Leigh syndrome (MILS) is a severe, early-onset neurodegenerative disorder affecting approximately 1 in 100,000 newborns. It is most commonly caused by pathogenic variants in the MT-ATP6 gene, which encodes a subunit of the mitochondrial ATP synthase complex essential for energy production. There are currently no targeted therapies available for MILS. Drug discovery in this field is hindered by the challenges in manipulating mtDNA, which limit the generation of accurate disease models. Through a cellular reprogramming approach, CureMILS has developed patient-specific neural models, including 2D cultures and 3D brain organoids, to investigate the biochemical and structural consequences of MT-ATP6 mutations. These models enabled the high-throughput screening of over 5,500 FDA-approved drugs in a drug repositioning effort. This strategy led to the identification of sildenafil as a promising candidate for the treatment of MILS. Following encouraging preclinical results, treatments in patients were conducted under compassionate use, supporting the granting of Orphan Drug Designation (ODD) for sildenafil in Leigh syndrome. This milestone paves the way for a multinational clinical trial to evaluate its therapeutic potential. Beyond its direct impact on MILS, CureMILS demonstrates a replicable paradigm for accelerating the development of therapies for other rare neuro-metabolic disorders by combining patient-derived cellular models with advanced drug repurposing strategies and multi-omics approaches.