Principal Investigator: José Luis Lanciego Pérez
Funding Organization: ERANET Neuron - MICINN
This consortium will carry out complementary translational research to propose a new therapeutic approach to Parkinson's disease with the possibility of beginning clinical trials in 3 to 5 years. The approach consists of a combination of innovative compounds that alleviate the symptoms of Parkinson's and minimize the side effects caused by current therapies. The focus includes the design of new compounds and new therapeutic approaches based on combinations of drugs and dual drugs to act on the heteromers of the G-protein coupled receptors.
The coordinator of the consortium has discovered trimers made up of D2 dopamine receptors, CB1 cannabinoid receptors, and A2A adenosine receptors in the corpus striatum, the target organ of the Parkinson's therapies, and has the necessary knowledge to detect abnormal trimers in Parkinson's. One member of the consortium has the necessary knowledge and skill to synthesize new patentable compounds for these receptors and even dual compounds that act simultaneously on two different receptors. The other two members of the consortium have pertinent knowledge of the development of Parkinson's models in animals, one in rats and the other in primates, and on the validation of new therapeutic approaches to Parkinson's.
What is required to begin phase-I clinical trials in humans is the validation of new therapies that act on the striatal receptors, first in rodents and then in primates.
Istituto Nazionale dei Tumori: Fondazione IRCCS; Rheinische Friedrich-Wilhelms-Universität Bonn; Universitat de Barcelona
We are currently facing enormous challenges in preventing and successfully treating neurodegenerative diseases. Traditional pharmacological approaches and approaches using stem cells have made some progress, but their impact continues to be limited.
As clinical results in Canavan's and Parkinson's disease suggest, gene transfer has considerable potential. However, this therapeutic intervention strategy also presents some unique obstacles: particularly the need to deal with viability, efficacy and safety. BrainCAV is based on the potential of type-2 canine adenovirus vectors (CAV-2), which perfectly transduce neurons and reach their target located at a considerable distance in a very efficient way by means of axonal transport. Furthermore, long-term episomal expression allows for safe and efficient neurospecific administration to the cell.
We have proposed a structured translational approach that includes basic research thanks to the viability, efficacy and safety of the preclinical model. To provide proof of principle of the efficacy of CAV-2, we use mucopolysaccharidosis type VII, a rare global disease that generally affects children, and Parkinson's disease, a focal degeneration of the dopaminergic neurons that usually affects the elderly.
In order to carry out this project, BrainCAV has brought together a multidisciplinary group of associates with unique knowledge, which will bring CAV-2 vectors to the threshold of clinical trials.
Università degli Studi di Milano; Fondazione Santa Lucia; Leibniz Institut für Neurobiologie; Institut National de la Santé et Recherche Médicale; Cardiff University; Lunds Universitet; University College London; Centre National de la Recherche Scientifique; European Parkinson's Disease Association; Xigen SA – XIGEN.
Principal Investigator: José Luis Lanciego Pérez
Funding Organization: European Commission - 7th Framework Program
Subsidized by the Program of the European Research Council - Advanced Grant
Neurodegenerative diseases are a considerable burden on the elderly population of Europe. Parkinson's disease affects 1.2 million people in Europe and, with the increase in life expectancy, this number will rise to increase pressure on healthcare systems.
Treatment of Parkinson's is symptomatic and there is an urgent need to find more efficient therapies. Degeneration of mesencephalic dopaminergic (DA) neurons trigger the initial phases of Parkinson's, which gives rise to the notion that cell replacement may be a long-term repair option for this neurological disease.
Indeed, previous studies in Parkinson's patients have shown that cell therapy has the potential to provide significant, long-lasting relief of symptoms. However, a weakness of these studies was the lack of an ideal source of transplantable human DA neurons. Recently, the production of induced pluripotent stem cells (iPSC) by reprogramming somatic cells has opened the door to the possibility of generating specific individual neurons with a high therapeutic potential.
We recently developed a methodology that promotes the transdifferentiation of mouse and human fibroblasts in functionally induced dopaminergic nerve cells (iDAN). The iDAN cells show complex neural properties, including pacemaker activity, synaptic integration, dopamine release based on activity and D2 functional autoreceptors. Therefore, iDAN cells provide a previously unknown source with ideal characteristics for cell therapy in Parkinson's, as they can be produced in patients in large quantities. Here, we propose improving the technology in humans and deciphering the molecular events.
We will then develop for in vivo reprogramming methods that locally promote neuron transdifferentiation in the mouse brain. Finally, we will attempt to perform autologous transplants of iDAN cells in monkeys with Parkinson's. Overall, this project will improve cell-reprogramming technologies and even aims to generate a better source of cells for transplant in patients with Parkinson's.
San Raffaele Scientific Institute