Drug Repurposing for Mitochondrial Disorders Using iPSCs Derived Neural Cells (cureMILS)
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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.
Full description
Leigh syndrome is a rare severe hereditary neurological disease that typically manifests during early childhood and is characterized by the progressive loss of motor and intellectual skills. A hallmark of the disease is the degeneration of neuronal cells in the brainstem and in the basal ganglia, particularly the dopaminergic neurons therein. The genetic underpinnings of this condition are multifaceted, encompassing mutations in both nuclear genes and in those contained within the mitochondrial DNA (mtDNA). The investigators hypothesize that these mutations share a common principle in their capacity to induce dysfunction of mitochondrial processes and of bioenergetic metabolism. The precise mechanism underlying neuronal death remains to be elucidated as researchers presently lack suitable disease models. Notably, the generation of a mouse model for mtDNA mutations has not been achieved, necessitating the exclusive reliance on patient derived material for research into the pathogenesis of these diseases. Moreover, there are currently no pathogenesis-based treatment approaches that have been demonstrated to improve patients' symptoms. Here, the investigators aim to utilize reprogramming technologies to engineer innovative human-derived disease models for research into Leigh syndrome. To this end, the investigators plan generating induced pluripotent stem cells (iPSCs) from fibroblasts of different Leigh syndrome patients who carry both nuclear (e.g. in SURF1) and mtDNA mutations (e.g. in MT-ATP6). Pluripotent progenitor cells offer a novel approach to better understand the pathogenesis of genetic diseases. In the case of Leigh syndrome, accessible cells, such as skin or blood cells, are almost never clinically affected. However, the nerve cells of the basal ganglia, which cannot be obtained via biopsies, are predominantly affected. The underlying mechanisms by which these dopaminergic neurons are particularly vulnerable to mitochondrial dysfunction and subsequent death remain to be elucidated. The objective of this study is to differentiate these induced pluripotent stem cells (iPSCs) into neural precursor cells (NPCs) and then into a neuronal cell population that is predominant inside the basal ganglia, such as dopaminergic neurons. Subsequently, a detailed analysis of these neurons will be conducted to ascertain mitochondrial and metabolic parameters, with the objective of elucidating neuronal changes associated with mitochondrial disease. Consequently, based on the identified dysfunction, imaging test procedures will be developed that are aimed at high sample throughput. This should enable high-throughput screening of molecule libraries on patient-specific iPSC-based neuronal cells for drug repurposing. The initial phase of the study has identified four potential metrics to be used for the screening of EMA and FDA approved drugs (repurposing): [1] measurement of the mitochondrial membrane potential using fluorophores, [2] measurement of calcium transients using fluorophores and reporter constructs, [3] measurement of the oxygen consumption rate (OCR) and the extracellular acidification rate (ECAR) using a Seahorse flux analyzer, and [4] investigation of the axonal outgrowth and branching patterns of the iPSC-derived neuronal cells by high-content screening. Compounds for which the investigators are able to confirm a positive effect by the above mentioned read-out methods will subsequently be provided to a selected number of patients for off-label compassionate use in cases where no standard treatment is available.
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Inclusion and exclusion criteria
Inclusion Criteria: 1. Patient has a disease causing mutation in one of the genes causing Leigh syndrome if mutated, 2. Patient has the characteristic cranial MRI abnormalities of Leigh syndrome
Exclusion Criteria: 1. bleeding disorder that precludes a skin biopsy, 2. retraction of consent
Trial design
80 participants in 2 patient groups
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Central trial contact
Alessandro Prigione, MD; Markus Schuelke, MD
Data sourced from clinicaltrials.gov
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