Project: Development of new small molecule compounds to treat mitochondrial dysfunction

Mitochondrial diseases are genetic disorders for which no cure is available. Patients suffer from a range of severely debilitating symptoms (Fig.1), which can ultimately result in death. The aim of this consortium is to develop a treatment for mitochondrial diseases. Besides the major impact mitochondrial diseases themselves have on patients and healthcare systems, it is important to realize that mitochondrial dysfunction plays an important role in several other major diseases. Therefore, the future spin-off is substantial._x000D__x000D_Mitochondria are present in every cell of our body, and serve as power plants, generating energy for the cell to exert its normal functions (Fig.2). This is done by the conversion of energy stored in food molecules into chemical energy that the cell can use, called adenosine 5’-triphosphate (ATP). ATP is produced in mitochondria in a energy conversion system called the respiratory chain. The respiratory chain consists of five complexes, which cooperate in a ‘conveyor-belt’-like process called oxidative phosphorylation (OXPHOS). Mitochondria also have a role in cell signalling, differentiation, and cell death. Therefore, mitochondrial dysfunction can have severe consequences throughout the body. Most prominently, cells cannot generate enough energy to support their functions and toxic by-products accumulate, resulting in further damage and even cell death._x000D__x000D_Mitochondrial diseases are severely debilitating genetic disorders, affecting the life, health and growth of affected children. The direct cause of these diseases is mitochondrial dysfunction. Mitochondrial diseases include Leigh disease, MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke), LHON (Leber’s hereditary optic neuropathy) and Friedrich Ataxia. Patients suffer from severe symptoms including muscle weakness, cramps, developmental delay, seizures, respiratory problems, blindness, extreme fatigue, gastrointestinal problems and loss of coordination. Mitochondrial diseases are classified as rare (orphan) diseases, affecting fewer than 200,000 individuals per disease category. However, when combined, approximately one in 4000 children are born with a mitochondrial disease, and another one in 4000 will develop mitochondrial disease by the age of ten. In addition, mitochondrial dysfunction plays an important role in various adult illnesses including Parkinson’s disease, diabetes, heart and kidney transplant dysfunction and cancer. Together, around 1.8 million people are affected by diseases related to mitochondrial dysfunction. These diseases are not only associated with considerable morbidity, but also have a major impact on the social life of the patient and their relatives, healthcare and economy. In addition, mitochondria are critically involved in ageing._x000D__x000D_Although our understanding of the biochemical and molecular bases of mitochondrial defects has improved, there is still no cure and treatment options are limited and inadequate. Available treatments include nutrition therapy, exercise and speech, physical and respiratory therapy, which can improve quality of life to certain extent. However, none of these treatments are truly effective. Patients often revert to freely available supplements (e.g. vitamins), which are ineffective and merely serve as ‘hope in a bottle’. There is an urgent need for clinically proven therapeutics to treat mitochondrial diseases._x000D__x000D_The aim of this consortium is to develop a novel therapy for the treatment of mitochondrial diseases, targeting Leigh disease, MELAS, LHON and Friedrich ataxia to achieve Proof-of-Concept (PoC). Once PoC has been established for these indications, the future spin-off market for other mitochondrial dysfunction related disorders is substantial._x000D__x000D_Funding by the EUROSTARS programme will enable the consortium to use its specific and complementary expertise in developing new effective compounds to treat mitochondrial diseases. Recently, Khondrion has identified several unique drug targets using its cell-based mitochondrial disease model developed in the past few years. In preliminary experiments, Khondrion has provided proof that intervention aimed at these targets can restore or prevent the negative consequences of mitochondrial dysfunction at a cellular level. In this project, the consortium will generate new compounds directed at these novel drug targets with high efficacy, bioavailability and stability, and few side-effects (tasks ElexoPharm and Pharmacelsus). New compounds will be tested for efficacy in unique cell-based and in vivo models for mitochondrial disease available at Khondrion and UMC St. Radboud Nijmegen (RUNMC). Best-performing new compounds will be characterized for exact mode of action. At the end of this project, new compounds will be available, with associated pre-clinical PoC data packages for the treatment of mitochondrial dysfunction. This allow for further development of these compounds with a prospective pharmaceutical company.

Acronym MITOTREAT (Reference Number: 6654)
Duration 01/01/2012 - 31/12/2014
Project Topic The aim of this project is to achieve Proof of Concept for the use of new compounds for the treatment of mitochondrial diseases, for which no cure exists. These new compounds will be designed, synthesized, tested (in vitro and in vivo efficacy, biological profile) and optimized in this project.
Project Results
(after finalisation)
The aim of the project was to generate a preclinical candidate compound for the treatment of mitochondrial diseases, in particular, Leigh syndrome, for which at the present time, no effective medicine is available. ElexoPharm has generated a patentable compound series with the most progressed compound, JP646, demonstrating Proof of Concept in a highly representative model for mitochondrial disease in mouse.
Network Eurostars
Call Eurostars Cut-Off 6

Project partner

Number Name Role Country
4 ElexoPharm GmbH Partner Germany
4 Pharmacelsus GmbH Partner Germany
4 Khondrion B.V. Coordinator Netherlands
4 University Medical Center St. Radboud Nijmegen Partner Netherlands