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Towards treatment of MELAS syndrome: drug development based on newly identified compounds

Projectomschrijving

Het project “op weg naar een behandeling voor het MELAS syndroom” heeft in de afgelopen zes jaar het gehele traject van het ontwikkelen van potentiele medicijnen tot aan de technische afronding van een klinische fase 2 succesvol doorlopen. Het MELAS syndroom is een van de
meest voorkomende vormen van een mitochondriële ziekte. Het syndroom wordt veroorzaakt door een mutatie in het DNA van de mitochondrien zelf (het mitochondriële DNA). De ziekte erft over via de moeder en heeft een wisselende expressie veroorzaakt door het fenomeen heteroplasmie waarbij in een cel zowel het normale DNA als het gemuteerde DNA in wisselende verhoudingen  aanwezig is. Pas bij een bepaald percentage gemuteerd DNA ontstaat ziekte. Door de mutatie ontstaat er stoornis (veelal een deficientie van het eerste enzym complex) in het oxidatieve fosforylering systeem. Als consequentie van deze deficientie ontstaan er teveel schadelijke zuurstofverbindingen en wordt het redox-metabolisme van de cel verstoord. Het mede binnen dit project ontwikkelde KH176 is in staat om deze negatieve consequenties op celnivo en in diermodellen te reduceren. KH176 is uitvoerig getest op onder andere veiligheid in gezonde volwassen mannen en is vervolgens in een fase 2 klinische studie getest in volwassen mannen en vrouwen met de m.3243A>G mutatie, de veroorzakende gen-mutatie in patienten met het MELAS/MIDD/mixed phenotype ziekte complex. Mede afhankelijk van de resultaten zal een
klinische fase 3 studie worden opgezet.

Producten

Titel: FDA grants Khondrion BV Orphan Drug Designation for treatment of inherited mitochondrial respiratory chain diseases
Titel: European Commission grants Orphan Drug Designation for Khondrion’s frontrunner compound KH176 for treatment of Leigh syndrome

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Samenvatting van de aanvraag

This project aims to develop a treatment for the rare genetic disorder MELAS (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes). MELAS is a rare disease with a prevalence of 1-5 per 10.000 individuals. Patients suffer from a range of severe clinical symptoms including seizures, muscle weakness, deafness, cardiomyopathy, diabetes, renal failure and developmental delay, which can ultimately lead to death. To date, no effective treatment for MELAS is available. MELAS is caused by mutations in the mitochondrial DNA (most commonly m.3243A>G) leading to mitochondrial dysfunction. Mitochondria are the cellular ‘power plants’ that convert food components (eg glucose) into energy for the cell, in the form of ATP (adenosine tri-phosphate), by a process known as oxidative phosphorylation (OXPHOS). In MELAS patients, this process is disturbed and mitochondria cannot produce sufficient ATP to support normal cell functions. In addition, potentially toxic biomolecules (incl. reactive oxygen species; ROS) can accumulate, causing disturbed cell signaling and oxidative damage. Because mitochondria are present in virtually every cell in the body, MELAS presents itself by a range of serious and debilitating symptoms affecting various organ systems. Several research lines headed by Prof.Smeitink at UMC St.Radboud Nijmegen (RUNMC) and at Khondrion BV have provided important insight into the mechanisms behind mitochondrial dysfunction and its cellular consequences. In recent studies, the group has been able to identify and validate several drug targets and compounds, which have proven very suitable for drug development. These compounds are specifically aimed at restoring and/or preventing the negative cellular consequences of mitochondrial dysfunction. Preliminary data by Khondrion BV show that 4 selected lead compounds can improve ATP production and reduce ROS levels in patient-derived cells. In addition, the compounds were able to normalize/mitigate several other aberrant parameters (complex I expression/activity, mitochondrial membrane potential & morphology). Preliminary experiments in a well-characterized mouse model for OXPHOS deficiency have shown efficacy in vivo as well. This project aims to translate these promising research results into an actual treatment for MELAS patients. To this end, the group of Prof.Smeitink at RUNMC will collaborate with leading industrial partners experienced in drug development (Drug Development Cluster, ie Mercachem BV, SEPS Pharma, NOTOX BV, Cambridge Major Laboratories Europe BV), dedicated live-cell high-content mitochondrial assays (Khondrion BV), regulatory affairs and clinical trial design for orphan diseases (PSR BV). This strong academic-industry consortium will allow this project to proceed through the first critical phases of drug development. First, the identified lead compounds will be optimized by medicinal chemistry to further improve efficacy and bioavailability. Efficacy of the optimized compounds will be determined using patient-derived cells in a unique in vitro model for mitochondrial (dys)function. For the selected best-performing compounds, in-depth mode-of-action studies will be performed (in vitro and in vivo using OXPHOS-deficient mice). Orphan drug designation will be applied for, and the final selected compound will enter a further drug development program, including GMP production and the required toxicology and formulation studies. Finally, a combined Phase I/II clinical trial will be performed to provide initial safety and efficacy data for the new compound-based drug in a limited group of MELAS patients. This project is supported by the two Dutch patient organizations active in mitochondrial diseases (“Volwassenen, Kinderen en Stofwisselingsziekten” and “Vereniging Spierziekten Nederland”) as well as “International Mito Patients”, a network of international patient organizations focusing on mitochondrial diseases. These organizations will actively collaborate in this project, including in defining clinical outcome measures related to quality of life, assisting in patient recruitment, organizing a European meeting for patients, researchers and clinicians, and creating information texts on mitochondrial diseases for patients and clinicians in different European languages (to be distributed via their websites and network). This project combines the expertise of leading scientists and clinicians in the field of mitochondrial dysfunction with the experience and focus of the industrial partners and patient organizations. This makes the aim of this ambitious multidisciplinary project feasible and realistic. The ultimate aim is to develop an effective treatment for MELAS patients, which would be a major breakthrough for patients, and the field of mitochondrial medicine as a whole. We anticipate that a treatment developed in this project will be available to patients (on market) 3-4 years after project finalization (within 10 years from now).

Onderwerpen

Kenmerken

Projectnummer:
113302003
Looptijd: 100%
Looptijd: 100 %
2012
2017
Onderdeel van programma:
Gerelateerde subsidieronde:
Projectleider en penvoerder:
Prof. dr. J.A.M. Smeitink
Verantwoordelijke organisatie:
Radboudumc