Journal Article

DKFZ-2026-00936

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Accelerating Leigh syndrome drug discovery through deep learning screening in brain organoids.

Menacho, C. ; Okawa, S. ; Álvarez-Merz, I. ; Wittich, A. ; Muñoz-Oreja, M. ; Lisowski, P. ; Martín, M. L. ; Pentimalli, T. M. ; Zakin, S. ; Thevandavakkam, M. ; Jerred, C. ; Lickfett, S. ; Petersilie, L. ; Rybak-Wolf, A. ; Seibt, A. ; Herebian, D. ; Inak, G. ; Brodesser, S. ; Zaliani, A. ; Mlody, B. ; Donnelly, J. ; Woleben, K. ; Soriano, F. X. ; Fernandez-Checa, J. C. ; Ventura, N. ; Cambridge, S. ; Mayatepek, E. ; Spinazzola, A. ; Schuelke, M. ; Rajewsky, N.DKFZ* ; Rossi, A. ; Peralvarez-Marin, A. ; Distelmaier, F. ; Perlstein, E. ; Holt, I. J. ; Puighermanal, E. ; Pless, O. ; Rose, C. R. ; Del Sol, A. ; Prigione, A.

2026
Springer Nature [London]

Abstract: Leigh syndrome (Leigh) is an untreatable mitochondrial disorder characterized by lactic acidosis and basal ganglia and midbrain pathology, leading to psychomotor regression and early death. We previously uncovered impaired neuronal morphogenesis in Leigh cerebral organoids carrying SURF1 gene variants. Leveraging this phenotype, we here develop a deep learning algorithm tailored for cell type-specific drug repurposing screening. In parallel, we perform a survival drug screen in a yeast model of Leigh. The two approaches independently converge on azole compounds, two of which - talarozole and sertaconazole - rescue neuronal morphogenesis in Leigh neurons and lower lactate release and improve growth rate in Leigh midbrain organoids. Mechanistically, these compounds modulate the retinoic acid pathway and membrane-associate lipid metabolism. The findings highlight azoles as promising candidates for Leigh and demonstrate the potential of combining in silico screens with human brain organoids as new approach methodologies (NAMs) to advance the discovery of therapeutics addressing rare neurodevelopmental disorders.

Keyword(s): Organoids: drug effects (MeSH) ; Organoids: metabolism (MeSH) ; Leigh Disease: drug therapy (MeSH) ; Leigh Disease: genetics (MeSH) ; Leigh Disease: pathology (MeSH) ; Leigh Disease: metabolism (MeSH) ; Humans (MeSH) ; Drug Discovery: methods (MeSH) ; Deep Learning (MeSH) ; Brain: drug effects (MeSH) ; Brain: metabolism (MeSH) ; Brain: pathology (MeSH) ; Neurons: drug effects (MeSH) ; Neurons: metabolism (MeSH) ; Drug Evaluation, Preclinical: methods (MeSH) ; Drug Repositioning: methods (MeSH) ; Membrane Proteins: genetics (MeSH) ; Membrane Proteins

Note: #DKTKZFB9# / #NCTZFB9

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Contributing Institute(s):

1. DKTK Koordinierungsstelle Berlin (BE01)
2. Koordinierungsstelle NCT Berlin (BR01)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2026

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