Final Report Summary - MITOTARGET (Mitochondrial dysfunction in neurodegenerative diseases: towards new therapeutics) The MITOTARGET project started on February 2009 and ended on March 2012 and completed thanks to the collaborative work of a consortium involving 18 institutional partners combining both expertise in clinical research and basic research under the leadership of the research intensive small and medium sized enterprise (SME) Trophos S.A. (Marseille, France). Mitochondria are the cell's power plant being responsible for the synthesis of the chemical form of energy called adenosine triphosphate (ATP) which is used by most living being. While its normal functions sustain cells' life, mitochondria are involved as well in cell death, being part of the apoptotic pathway - apoptosis being also known as a cell suicide. In some cases, the balance between life and death at the mitochondrial level is dysfunctioning and cells either doesn't apply a message of death received leading to improved abnormal cell survival, which is cancer - or the apoptotic program is run without any message of death leading to neurodegenerative process. A first aim of the MITOTARGET project was therefore to gain a more comprehensive insight into the mechanisms leading to mitochondrial dysfunction and thereby the neuronal dysfunctions associated with neurodegenerative diseases. A second aim was to establish if these mechanisms are amenable to therapeutic intervention in humans, employing a new class of therapeutic agent targeting the underlying mitochondrial dysfunction in neurons or their supporting cells. Those two objectives were reached by combining the expertise of both basic research scientists, specialists of the involvement of mitochondria in neurodegenerative diseases (Alzheimer's disease (AD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) and ageing), and clinical neurologists with a significant experience in the assessment of drug efficacy in ALS (also known as Lou Gehrig's disease, motor neuron disease or Charcot's disease). Indeed, the basic research group explored the impact of a group of neurodegenerative diseases on the mitochondrial functions namely their ability to move and fuse or separate themselves in the cell (dynamics), their lipid membrane properties, their ability to modulate the energy production and to generate harmful reactive oxygen species and their involvement in the overall apoptotic pathways. In the meantime, the clinical research team assessed the ability of a newly discovered mitochondrial targeted compound named olesoxime to delay motor neuron death in 512 ALS patients enroled in a P2/3 clinical study conducted in 15 hospitals across 5 European countries. Key results of the project are that while mitochondria are confirmed as being key players in the neurodegenerative process, it appears that the mechanisms involved varies from a disease to another with the compound olesoxime giving promising results to rescue neurons of cell death in those models. However, the consortium faced a disappointing result in the clinic not succeeding to prove the efficacy of olesoxime for the treatment of ALS, but still proving that it was safe and well tolerated in patients. Those results taken with the results from other groups published over the last three years, strongly advocate for a review of the experimental protocols used in preclinical models and the relevance of the models themselves. It also highlights the urgent need for relvant biomarkers allowing the assessment of the efficacy of neuroprotective / restorative drugs in neurodegenerative diseases. Project context and objectives: MITOTARGET was aimed at understanding the interplay between mitochondrial dysfunction and neuronal activity in order to gain a further insight into plasticity and brain pathophysiology under various neurodegenerative conditions. The acquired knowledge will be used to further develop new therapeutic strategies to improve mitochondrial function in neurons affected by these deadly and highly debilitating diseases. Mitochondria are membrane bound organelles whose principal function is to provide energy for the cell in the form of ATP through the oxidative phosphorylation complexes located on the inner mitochondrial membrane. Neurons need large amounts of ATP to control the intracellular ionic homeostasis required to regulate neurotransmission. Moreover, many proteins and processes critical for brain plasticity require ATP including cytoskeletal components involved in axoplasmic transport (microtubules, actin filament, kinesins, myosins, etc.), ion-motive ATPases and a myriad of protein phosphorylation reactions. Since most of the ATP produced in neurons comes from oxidative phosphorylation, neurons are critically dependant on mitochondrial function and oxygen supply. In addition to ATP synthesis, mitochondria are key regulators of calcium homeostasis, free radical production, steroid synthesis and apoptosis, each of these factors could also be associated with essential mechanisms involved in neurodegenerative diseases along with mechanisms regulating neuronal and synaptic plasticity. Hence, considering the importance of mitochondrial functions in neurons, it is hypothesised that dysfunction of mitochondria acts causally in the loss of brain plasticity, synaptic impairment, axonal injury and neuronal loss, all of which are major hallmarks of neurodegenerative diseases. In order to further explore this hypothesis, the MITOTARGET partners used drug candidates from a newly identified chemical family of mitochondrial targeted compounds developed by Trophos. These compounds employed as pharmacological tools provided the opportunity to better understand the role of mitochondrial impairments in neurodegenerative diseases. The research and technological development (RTD) program of MITOTARGET aimed at demonstrating that relevant mitochondrial mechanisms are addressable in various neurodegenerative processes. The demonstration part of MITOTARGET aimed at establishing the clinical efficacy of mitochondrial-targeted compounds in ALS patients. The information gained from MITOTARGET will provide the basis for further development of novel classes of neuroprotective drug candidates and treatment for therapeutic indications ranging from ALS through to many other neurological disorders such as AD, HD, hereditary spastic paraplegia (HSP), Parkinson's disease (PD), multiple sclerosis (MS) or aging in a later stage. Basic research objectives: - Characterise defects in mitochondrial axonal transport and morphological changes during the course of neurodegenerative diseases. - Determine the role of mitochondrial membrane fluidity in the control of mitochondrial function and dysfunction. - Define the role of mitochondrial dysfunctions in the generation of oxidative stress and explore potential markers of oxidative damage as biomarkers of mitochondrial dysfunction. - Dissect the mitochondrial apoptotic pathways mainly focusing on the involvement of the mitochondrial permeability transition pore in the context of neurodegeneration. - Evaluate the ability of a new class of compounds targeted to the mitochondria to correct mitochondrial dysfunctions and to promote neuron survival and axonal growth in vivo. Translational clinical and industrial development objectives: - Complete a clinical phase II study of efficacy of a first in class compound targeting the mitochondria (TRO19622) to evaluate its ability to improve survival and motor function in ALS patients. Project results: Key results: - Mitochondrial axonal transport is impaired in different familial forms of ALS, as well as in AD and HD cell models; the motor protein kinesin1 plays a key role in the proper maintenance of mitochondria transport toward the distal part of the axon. - Changes in mitochondrial membrane fluidity are variable depending on the disease or genetic defect; while mitochondrial membrane fluidity decreased with age and in ALS and AD brains, fluidity increases in neurons expressing mutant huntingtin. - Mitochondrial associated membranes (MAMs) are modulators of intracellular Ca2+ homeostasis in ALS models. - Olesoxime promotes neuronal survival by preventing mitochondrial apoptotic pathways and improves mitochondrial function in many neurodegenerative disease cell models. - Beyond mitochondria, olesoxime promotes microtubule dynamics. - Promising, beneficial effects were obtained in HD and AD preclinical models. - Olesoxime proved to be safe and well tolerated in a large scale study. Potential impact: The MITOTARGET project has provided very interesting new information on the common and different mitochondrial features present in various adult-onset neurodegenerative diseases. This information will be useful for the development of new therapeutic strategies based on maintaining or improving mitochondrial integrity and function. Besides, commercial opportunities arising from the results of the MITOTARGET project are mainly driven by the work done on olesoxime. As an example of such opportunities, Trophos signed in 2010, as a result of the ongoing MITOTARGET clinical trial, a strategic partnership agreement with the Swiss biotech company Actelion, with the aim to be able to have the product registered and marketed in case of success of the MITOTARGET clinical trial. This partnership was essential for Trophos since it allowed boosting the development of the compound, successfully filling-in the regulatory and development gaps that were seen as hurdles for the registration of the product in both United States (US) and European markets. In addition, this strategic partnership would have given access to an already deployed sales force able to address both major markets and ultimately speeding up the drug's availability to the patients. Unfortunately, following the disappointing results of the clinical trial, Actelion decided to drop-out this partnership - still Trophos remains now with the experience of negotiation of such agreements and relationship with key players within the pharmaceutical industry. In spite of the null result of the clinical trial using the drug in ALS patients, olesoxime has been shown to be safe and well tolerated in a large multicenter trial with a total exceeding 900 patients or healthy volunteers who were exposed to the drug. In addition, the results obtained in the basic research part of the project support both the hypothesis that the drug doesn't have a mechanism of action suitable for slowing the progression of ALS in diagnosed patients and that it may still be efficacious in other diseases with diagnosis and progression compatible with therapeutic intervention at earlier stage of the neurodegenerative process (e.g. multiple sclerosis or Huntington's disease). On top of that, it should be kept in mind that many drugs that are now on the market were initially not developed for the indication those are marketed for. Hence, it is Trophos team belief that olesoxime remains a drug of interest for the treatment of neurodegenerative diseases. Based on both the good non clinical pharmacology dataset generated during the project as well as the good safety data generated by the clinical trial, Trophos therefore plans to test olesoxime in a setting that would benefit from its efficacy on decreasing the impact of early events leading to neuronal death and subsequent cognitive impairments and / or disability. Having reviewed the new pharmacology data collected on olesoxime over the last three years, it seems to us that the best indication candidate for such new test of olesoxime would be multiple sclerosis. Indeed, on top of the data gathered in the frame of the MITOTARGET project, which again strongly advocate for an efficacy in models of early neurodegeneration, Trophos and its research partners, worked together on relevant models of neurodegeneration in multiple sclerosis. The results from these studies consistently show that olesoxime provides a significant benefit in relevant MS models by providing both neuroprotection as illustrated by the MITOTARGET results, but also through the improvement of the remyelination process (Magalon et al., 2012). List of websites: http://www.mitotarget.eu Project coordinator: Dr Rebecca Pruss, Trophos S.A. email: rpruss@trophos.com Project co-PI / basic research: Dr Thierry Bordet, Trophos S.A. email: tbordet@trophos.com Project co-PI / clinical research: Dr Pascal Longlade, Trophos S.A. email:plonglade@trophos.com Project manager: Mr Julien Veys, Trophos S.A. email:jveys@trophos.com Documentos relacionados Final Report - MITOTARGET (Mitochondrial dysfunction in neurodegenerative diseases: towards new therapeutics)
