Drug Repurposing for Mitochondrial Disorders Using iPSCs Derived Neural Cells

Condition(s) studied

Investigational drug(s) / intervention(s)

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

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

blood drawing: 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.

off-label compassionate drug use: 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.

Study 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.

Eligibility

Primary outcome measure(s)

• Reduction of the increased mitochondrial membrane potential — 1 year
  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.

Trial sites (2)

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