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

Acronym	CureMILS (Reference Number: EJPRD20-010)
Project Topic	Mitochondrial DNA (mtDNA)-associated Leigh syndrome (MILS) is an untreatable brain disease affecting 1/100,000 newborns. MILS is typically caused by mtDNA mutations in the ATP-generating subunit MT-ATP6. Drug discovery is particularly challenging for MILS. The limited access to patient neural tissue and the impossibility to engineer mtDNA hinder the development of the cellular and animal models needed for treatment discovery. Our consortium will employ neural cells generated from MILS patients via cellular reprogramming to carry out large-scale screenings using repurposable drugs, thereby allowing the identification of therapeutic strategies. Our proof-of-concept study demonstrated that this approach is feasible and relevant. After screening 150 FDA-approved compounds, we identified phosphodiesterase 5 inhibitors (PDE5i) as a potential therapy for MILS. Compassionate use of PDE5i is now proving to be beneficial in a MILS patient. We propose to extend this approach using the largest available library of repurposable compounds (8,000). We will validate hit compounds by combining mitochondrial profiling with multi-omics analysis using reprogramming-derived neural models (neural progenitors, neurons, and brain organoids) from different MILS patients. Our consortium will identify drugs suited for repositioning as interventions in MILS, laying the foundation for a multi-national clinical trial and a concrete path towards a cure for MILS. Moreover, we will establish a paradigmatic working pipeline for reprogramming-driven drug discovery of rare neurological disorders.
Network	EJP RD
Call	2nd EJP RD Joint Transnational Call for Rare Diseases Research Project (JTC 2020)

Project partner

Number	Name	Role	Country
1	University Hospital Düsseldorf (UKD)	Coordinator	Germany
2	Center for Molecular Neurobiology Hamburg (ZMNH)	Partner	Germany
3	Institute of Molecular Biology	Partner	Austria
4	RIMLS	Partner	Netherlands
5	Biomedicum	Partner	Finland
6	Institute of Genetics and Animal Breeding	Partner	Poland
7	Pharmacology	Partner	Italy
8	Luxembourg Centre for Systems Biomedicine	Partner	Luxembourg
9	International Mito Patients (IMP)	Partner	Netherlands
10	Charité University	Observer	Germany
11	University Children's Hospital, Heinrich Heine University (HHU)	Observer	Germany
12	Radboud University Medical Centre	Observer	Netherlands
13	Oroboros Instruments GmbH High-Resolution Respirometry	Observer	Austria
14	Foundation IRCCS Neurological Institute C. Besta	Observer	Italy
15	University of Milan	Observer	Italy
16	Max Planck Institute for Molecular Genetics	Observer	Germany
17	Deutsches MITONET e.V.	Observer	Germany