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New Challenges to treating Parkinson's disease, novel emerging agents and targets for potential treatments....

by Wassilios Meissner

Priorities in Parkinson's disease research
Wassilios G. Meissner, Mark Frasier, Thomas Gasser, Christopher G. Goetz, Andres Lozano, Paola Piccini, José A. Obeso, Olivier Rascol, Anthony Schapira, Valerie Voon, David M. Weiner, François Tison and Erwan Bezard
Nature Reviews / Drug Discovery Volume 10 / Mai 2011/377------ [ PubMed link ]


Wassilios Meissner est praticien hospitalier au CHU Pellegrin de Bordeaux et chercheur dans l'équipe " Physiopathologie des syndromes parkinsoniens" d' Erwan Bezard à l'Institut des Maladies Neurodégénératives .


Abstract |
The loss of dopaminergic neurons in the substantia nigra pars compacta leads to the characteristic motor symptoms of Parkinson's disease: bradykinesia, rigidity and resting tremors. Although these symptoms can be improved using currently available dopamine replacement strategies, there is still a need to improve current strategies of treating these symptoms, together with a need to alleviate non-motor symptoms of the disease. Moreover, treatments that provide neuroprotection and/or disease-modifying effects remain an urgent unmet clinical need. This Review describes the most promising biological targets and therapeutic agents that are currently being assessed to address these treatment goals. Progress will rely on understanding genetic mutations or susceptibility factors that lead to Parkinson's disease, better translation between preclinical animal models and clinical research, and improving the design of future clinical trials.


FBN

Wassilios Meissner
What is the current treatment landscape in PD? How can we better tackle unmet treatment needs, e.g. disease-modification or neuroprotection?


Wassilios Meissner
Current therapeutic development in PD includes approaches such as re-formulations of existing drugs which are approved for PD, re-positioning of compounds approved for other indications and development of novel small molecule and gene therapy approaches. Many of the therapies under current development are focused on improvement of motor control, fluctuations, and dyskinesias. Far fewer approaches address the other two key unmet clinical needs, specifically alleviating non-motor symptoms and disease modification/neuroprotection. With regard to the latter, strategies targeting alpha-synuclein using drugs or passive immunization are promising approaches in PD, but the translational value of current pre-clinical models remains unsatisfactory since they do not adequately capture the progressive nature of neither the disease nor its extension from dopaminergic to non-dopaminergic involvement. Another promising approach is investigating of how genetic mutations lead to PD. It is hoped that pathophysiological insights from the identification of the role of genetic mutations that are responsible for hereditary forms of PD will uncover novel drug targets, and that future therapies targeted towards them will have broader efficacy against sporadic PD than currently available symptomatic treatments.

FBN
What is in the PD treatment pipeline for better controlling motor and non-motor symptoms?

Wassilios Meissner
Although a main aim is to find agents that are disease-modifying or neuroprotective, in the shorter term it is necessary to also find agents that improve symptoms. Safinamide (sodium channel inhibitor, monoamine oxidase B inhibitor and glutamate release inhibitor), pardoprunox (5-HT1A receptor agonist and partial D2/D3 receptor agonist) and IPX066 (new levodopa formulation) are the most advanced compounds in drug development for motor symptoms, while pitolisant (histamine H3 inverse receptor agonist) is currently being tested for fatigue in several phase III trials.

The blood barrier remains a critical obstacle for treatment development in PD. Agents that do not cross the blood brain barrier have to be delivered stereotactically. This approach has been used in PD for the delivery of glutamic acid decarboxylase (GAD) to the subthalamic nucleus through gene transfer. Indeed, PD patients receiving GAD delivery showed sustained benefits on motor symptoms. Intraputaminal delivery of the three main enzymes responsible for dopamine synthesis restored extracellular dopamine levels and improved motor signs in non-human primates. An open-label phase I study in PD patients is ongoing.

Smart-deep brain stimulation techniques are also under development. These techniques will, in its final form, allow individualized on-demand modulation of abnormal activity in basal ganglia-cortical networks in PD patients.

FBN
Are currently any compounds or interventions being tested for disease-modification or neuroprotection in PD?

Wassilios Meissner
Ongoing studies investigating disease-modifying or neuroprotective properties include the mitochondrial modulators creatine and coenzyme Q, as well as the L-type calcium antagonist isradipine. Green tea polyphenols and deferiprone, an iron chelator, both of which are believed to decrease oxidative stress, are also under investigation. Finally, the effects of neurotrophic factors or modulators on disease progression, either stereotactically delivered or orally given, are currently being assessed.

FBN
Beyond the identification of new compounds and treatment targets, what hurdles need to be overcome to achieve disease-modification or neuroprotection in PD?

Wassilios Meissner
It is not very likely that therapies based on single drugs will provide measurable disease modification or neuroprotection in PD. Rather, a combination of compounds that interfere simultaneously with different key events of PD pathology seems to be the most promising strategy. This approach would however, require collaboration between the pharmaceutical companies that hold the rights of the different compounds.
The development of objective endpoints based on imaging, cerebrospinal fluid/blood biomarkers or other techniques will be crucial for the success of future disease-modification or neuroprotection trials in PD. It is unlikely that a single marker will provide sufficient sensitivity and specificity and a combination of different biomarkers seems to be the most promising strategy. Beyond current sampling techniques, new tools, e.g. colonic or skin biopsy, may help identifying and validating new targets.
Lastly, non-motor outcomes (such as falls, cognitive impairment or quality in life), if they display the appropriate metrics, should be utilized to assess disease-modification and neuroprotection in PD.

Merci Wassilios / pour Bordeaux Neurosciences Mai 2011

 


Com FBN Yves Deris 17 Mai 2011