Drug Repurposing for Mitochondrial Disorders Using iPSCs Derived Neural Cells

NCT06967831 | Recruiting

• 1 other identifier: EA2_131_13
• Study Type: observational
• Target: 80
• Locations: 1 country
• Sites: 2

Brief Summary

In this project, the investigators are using iPSC lines derived from patients with Leigh syndrome that carry mutations in the mitochondrial (mtDNA) and in the nuclear DNA (nDNA) to reprogram them into neural progenitor cells and into dopaminergic neurons. The researchers are using this experimental system to screen FDA (Food and Drug Administration, USA) and EMA (European Medicines Agency) approved drugs for a positive effect on Leigh patient-derived neuronal cells (drug repurposing) using various biochemical, optic, and morphological outcome measures. Confirmed positive hits may be used for compassionate off-label use in Leigh patients when no standard treatment is available.

Conditions

Leigh Syndrome (Maternally Inherited, MILS); Leigh Syndrome (AR, AD, XR)

Keywords

mitochondrial disease; drug repurposing; Leigh syndrome; iPSC derived neural cells; off-label compassionate use; dopaminergic neurons; neuronal precursor cells; maternal inheritance; autosomal recessive inheritance; autosomal dominant inheritance; X-chromosomal recessive inheritance

Outcome Measures

Primary Outcomes (1)

• Reduction of the increased mitochondrial membrane potential

  The investigators will measure the mitochondrial membrane potential in Leigh patient iPSC-derived neural cells. If the membrane potential can be normalized, a drug will be considered a positive hit. The membrane potential will be determined indirectly by the fluorescence intensity measurement of a membrane potential sensitive dye (TMRM). The patients' fluorescence readings will be compared to the fluorescence readings of neural cells that have been generated from healthy control iPSCs.

  1 year

Secondary Outcomes (2)

• Reconstitution of the neural outgrowth pattern

  1 year

• Measuring calcium transients in iPSC derived neural cells

  1 year

Study Arms (2)

Leigh Syndrome (Maternally Inherited, MILS)

Patients with Leigh syndrome carrying disease-causing mutations in their mtDNA. This subtype of Leigh syndrome is called Maternally Inherited Leigh Syndrome (MILS)

Procedure: skin biopsy; Other: generation of iPSCs; Diagnostic Test: blood drawing; Drug: off-label compassionate drug use

Leigh Syndrome (AR, AD, XR)

Patients with mitochondrial diseases that are caused by mutations in the nuclear DNA, which may be inherited in an autosomal recessive (AR), autosomal dominant (AD), or X-chromosomal recessive (XR) mode of inheritance.

Procedure: skin biopsy; Other: generation of iPSCs; Diagnostic Test: blood drawing; Drug: off-label compassionate drug use

Interventions

skin biopsy PROCEDURE

Taking a punch skin biopsy of 3 mm diameter under local anesthesia and culturing skin fibroblasts from them.

Leigh Syndrome (AR, AD, XR); Leigh Syndrome (Maternally Inherited, MILS)

generation of iPSCs OTHER

Using cultured skin fibroblasts of the patients, iPSCs will be generated according to standard procedures.

Leigh Syndrome (AR, AD, XR); Leigh Syndrome (Maternally Inherited, MILS)

blood drawing DIAGNOSTIC_TEST

Drawing blood from a peripheral vein for DNA and RNA isolation. The degree of heteroplasmy (mutation load) for the mtDNA mutation will be determined in the blood DNA.

Leigh Syndrome (AR, AD, XR); Leigh Syndrome (Maternally Inherited, MILS)

off-label compassionate drug use DRUG

In case the investigators identify a positive hit during drug repurposing with FDA and EMA approved substances, they will offer it as off-label compassionate use to patients for whom no standard treatment is available.

Leigh Syndrome (AR, AD, XR); Leigh Syndrome (Maternally Inherited, MILS)

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Patients (male and female) who are affected by Leigh syndrome and carry a pathogenic mutation in a gene known to be associated with Leigh syndrome

Sponsors & Collaborators

• Charite University, Berlin, Germany: lead
• European Union: collaborator
• German Research Foundation: collaborator
• German Federal Ministry of Education and Research: collaborator

Study Sites (2)

Universitätsklinikum Düsseldorf

Düsseldorf, North Rhine-Westphalia, 40225, Germany

RECRUITING

Charite - Universtaetsmedizin Berlin

Berlin, State of Berlin, 13353, Germany

RECRUITING

Related Publications (6)

• Lorenz C, Lesimple P, Bukowiecki R, Zink A, Inak G, Mlody B, Singh M, Semtner M, Mah N, Aure K, Leong M, Zabiegalov O, Lyras EM, Pfiffer V, Fauler B, Eichhorst J, Wiesner B, Huebner N, Priller J, Mielke T, Meierhofer D, Izsvak Z, Meier JC, Bouillaud F, Adjaye J, Schuelke M, Wanker EE, Lombes A, Prigione A. Human iPSC-Derived Neural Progenitors Are an Effective Drug Discovery Model for Neurological mtDNA Disorders. Cell Stem Cell. 2017 May 4;20(5):659-674.e9. doi: 10.1016/j.stem.2016.12.013. Epub 2017 Jan 26.

  PMID: 28132834 BACKGROUND

• Henke MT, Zink A, Diecke S, Prigione A, Schuelke M. Generation of two mother-child pairs of iPSCs from maternally inherited Leigh syndrome patients with m.8993 T > G and m.9176 T > G MT-ATP6 mutations. Stem Cell Res. 2023 Mar;67:103030. doi: 10.1016/j.scr.2023.103030. Epub 2023 Jan 17.

  PMID: 36669241 BACKGROUND

• Steiner T, Zink A, Henke MT, Cecchetto G, Buenning M, Rossi A, Schuelke M, Prigione A. RNA-based generation of iPSCs from a boy carrying the mutation m.9185 T>C in the mitochondrial gene MT-ATP6 and from his healthy mother. Stem Cell Res. 2022 Oct;64:102920. doi: 10.1016/j.scr.2022.102920. Epub 2022 Sep 15.

  PMID: 36137325 BACKGROUND

• Carli S, Levarlet A, Diodato D, Bertini ES, Martinelli D, Malandrini A, Lopergolo D, Gallus GN, Ganetzky RD, La Morgia C, Carelli V, Primiano G, Dominguez-Gonzalez C, Serrano-Lorenzo P, Martin MA, Ardissone A, Lamperti C, Nicoletta V, Klopstock T, Distelmaier F, Zeng L, Buchner B, Mancuso M, Schuelke M, Prigione A, Garone C. Natural History of Patients With Mitochondrial ATPase Deficiency Due to Pathogenic Variants of MT-ATP6 and MT-ATP8. Neurology. 2025 Apr;104(7):e213462. doi: 10.1212/WNL.0000000000213462. Epub 2025 Mar 20.

  PMID: 40112238 BACKGROUND

• Diodato D, Schiff M, Cohen BH, Bertini E, Rahman S; Workshop participants. 258th ENMC international workshop Leigh syndrome spectrum: genetic causes, natural history and preparing for clinical trials 25-27 March 2022, Hoofddorp, Amsterdam, The Netherlands. Neuromuscul Disord. 2023 Aug;33(8):700-709. doi: 10.1016/j.nmd.2023.06.002. Epub 2023 Jun 15. No abstract available.

  PMID: 37541860 BACKGROUND

• Inak G, Rybak-Wolf A, Lisowski P, Pentimalli TM, Juttner R, Glazar P, Uppal K, Bottani E, Brunetti D, Secker C, Zink A, Meierhofer D, Henke MT, Dey M, Ciptasari U, Mlody B, Hahn T, Berruezo-Llacuna M, Karaiskos N, Di Virgilio M, Mayr JA, Wortmann SB, Priller J, Gotthardt M, Jones DP, Mayatepek E, Stenzel W, Diecke S, Kuhn R, Wanker EE, Rajewsky N, Schuelke M, Prigione A. Defective metabolic programming impairs early neuronal morphogenesis in neural cultures and an organoid model of Leigh syndrome. Nat Commun. 2021 Mar 26;12(1):1929. doi: 10.1038/s41467-021-22117-z.

  PMID: 33771987 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

\[1\] human induced pluripotent stem cells (hiPSC) generated from fibroblasts or from blood blood cells of patients with Leigh syndrome. \[2\] DNA samples extracted from white blood cells of patients with Leigh syndrome. \[3\] RNA samples extracted from white blood cells, from cultured skin fibroblasts and from iPSC-derived neural cells of patients with Leigh syndrome.

MeSH Terms

Conditions

Leigh Disease; Mitochondrial Diseases; Multiple Pterygium Syndrome, Autosomal Dominant

Interventions

Blood Specimen Collection

Condition Hierarchy (Ancestors)

Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pyruvate Metabolism, Inborn Errors; Carbohydrate Metabolism, Inborn Errors; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Investigative Techniques

Study Officials

• Markus Schuelke, MD

  CHARITE - UNIVERSITAETSMEDIZIN BERLIN

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Markus Schuelke, MD

CONTACT

+49 30 4505 66112; markus.schuelke@charite.de

Alessandro Prigione, MD

CONTACT

+49 211 81 17687; alessandro.prigione@hhu.de

Study Design

• Study Type: observational
• Observational Model: CASE ONLY
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Neuropediatrics

Study Record Dates

• First Submitted: April 20, 2025
• First Posted: May 13, 2025
• Study Start: March 1, 2020
• Primary Completion (Estimated): February 28, 2030
• Study Completion (Estimated): February 28, 2030
• Last Updated: May 13, 2025

Record last verified: 2025-05

Locations

DE (2)