Nature Communications

Accelerating Leigh syndrome drug discovery through deep learning screening in brain organoids

C Carmen Menacho S Satoshi Okawa I Iris Álvarez-Merz A Annika Wittich M Mikel Muñoz-Oreja P Pawel Lisowski M Mario López Martín T Tancredi Massimo Pentimalli S Shiri Zakin M Mathuravani Thevandavakkam C Caleb Jerred S Selene Lickfett L Laura Petersilie A Agnieszka Rybak-Wolf A Annette Seibt D Diran Herebian G Gizem Inak S Susanne Brodesser A Andrea Zaliani B Barbara Mlody J Justin Donnelly K Kasey Woleben F Francesc Xavier Soriano J Jose C. Fernandez-Checa N Natascia Ventura S Sidney Cambridge E Ertan Mayatepek A Antonella Spinazzola M Markus Schuelke N Nikolaus Rajewsky A Andrea Rossi (Genome Engineering and Model Development Lab, Institut für umweltmedizinische Forschung-Leibniz Research Institute for Environmental Medicine) A Alex Peralvarez-Marin F Felix Distelmaier E Ethan Perlstein I Ian J. Holt E Emma Puighermanal O Ole Pless C Christine R. Rose A Antonio Del Sol A Alessandro Prigione

Abstract

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.

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Article Details

Volume / Issue Vol. 17, Issue 1
Published April 20, 2026
ISSN 2041-1723
Publisher Nature Portfolio

Journal Info

Nature Communications

Nature Portfolio
ISSN: 2041-1723 Open Access Life Sciences

Authors (40)

C

Carmen Menacho

S

Satoshi Okawa

I

Iris Álvarez-Merz

A

Annika Wittich

M

Mikel Muñoz-Oreja

P

Pawel Lisowski

M

Mario López Martín

T

Tancredi Massimo Pentimalli

S

Shiri Zakin

M

Mathuravani Thevandavakkam

C

Caleb Jerred

S

Selene Lickfett

L

Laura Petersilie

A

Agnieszka Rybak-Wolf

A

Annette Seibt

D

Diran Herebian

G

Gizem Inak

S

Susanne Brodesser

A

Andrea Zaliani

B

Barbara Mlody

J

Justin Donnelly

K

Kasey Woleben

F

Francesc Xavier Soriano

J

Jose C. Fernandez-Checa

N

Natascia Ventura

S

Sidney Cambridge

E

Ertan Mayatepek

A

Antonella Spinazzola

M

Markus Schuelke

N

Nikolaus Rajewsky

A

Andrea Rossi

Genome Engineering and Model Development Lab, Institut für umweltmedizinische Forschung-Leibniz Research Institute for Environmental Medicine

A

Alex Peralvarez-Marin

F

Felix Distelmaier

E

Ethan Perlstein

I

Ian J. Holt

E

Emma Puighermanal

O

Ole Pless

C

Christine R. Rose

A

Antonio Del Sol

A

Alessandro Prigione

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