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Cell permeable peptides as drug delivery system: a way towards innovative therapeutic strategies for neurodegeneration

Final Report Summary - CPADS (Cell permeable peptides as drug delivery system: a way towards innovative therapeutic strategies for neurodegeneration)

The project CPADS (see http// online) has been designed to foster a dynamic pathway between academic research organisations and private commercial enterprises, based on a longer term cooperation programme in the field of innovative therapeutic strategies for neurodegenerative disorders.

Currently, the major disorders of central nervous system affect one in three people in the developed world, and brain diseases are among the most prevalent and debilitating diseases. Because most of these disorders are chronic, the individual's quality of life and socio-economic prospect are dramatically impaired.

Studies recently published by European Brain Council (Gustavsson et al., Eur. J. Neurol. 2012, 19 (1): 155-162; DiLuca et al., EJN , 2011, 33(5):768-818) declare that Europe spends more on brain disorders than on cardiovascular diseases and cancer combined, being the value, including direct and indirect costs, equal to EUR 798 billion. These costs will continue to rise as European population live longer, thus brain disorders represents the number one economic challenge for European healthcare now and in the future. At present 514 million of European citizens are living with a brain disorder. Thus, the project holds the potential to have a dramatic effect on the level of disability in European Union (EU) populations.

The project involved two academic partners, University of Milano and IRFMN which brought to the consortium their deep knowledge on molecular pathogenic event in neurodegenerative diseases, and two academic partners which participated to the consortium in two different phases, Xigen (phase 1) with a strong expertise in the design and synthesis of cell permeable peptides, and CisBio (phase 2) leaders in new technology to visualise protein-protein interaction and to develop innovative protocols for measuring intracellular kinase activity.

In fact, through inter-sectorial industry-academia collaboration, the proposal explored novel technologies to target key protein-protein interactions and key intracellular pathways mediating neurodegeneration and cell death, addressing both the creation of innovative models and the design of innovative drugs by means of exploiting the use of cell-permeable peptides (CPP). The main science and technology objective of the proposed research programme was to develop cell-permeable peptides to manipulate biological pathways involved in degenerative events leading to neuronal cell-death. In the frame of the CPADS project protein complexes of relevance for paradigmatic neurodegenerative diseases such as Alzheimer and Parkinson disease have been identified and characterise d and cell permeable peptides have been exploited as potential treatment for diseases.

The project started in 1 March 2008. A fruitful collaboration and constant flux of technical exchanges occurred among partners. Since the major outcome of CPADS was producing and exploiting CPP in neurodegenerative disease, both to generate innovative animal models and to find innovative therapies, a list of potential CPP has been created, including peptides derived from in vitro studies of key intracellular pathways for neurodegeneration performed in CO1 UMIL and P3 IRFMN. In the frame of CPADS we have produced more than 12 peptides attached to Tat moiety raised against key protein complexes and signalling pathways involved in neurodegeneration and some of them have been produced in large scale. 'Lead' peptides have been identified in the first 24 months and they have been tested for efficacy in vivo either to generate innovative animal models of a paradigmatic neurodegenerative disease, i.e. Alzheimer disease, or to rescue altered functions in established transgenic models of neurodegeneration.

Results obtained highlighted the key importance of D-JNKI1 peptide as a rescuing treatment in Alzheimer disease and NR2A/PSD95 competing peptide as key in rescuing motor behaviour and decreasing dyskinesia in experimental parkinsonism. These Tat-peptides will be further exploited for their potential clinical use and tested in different models of both Alzheimer and Parkinson disease.

In addition, an innovative non-trasgenic animal model of sporadic Alzheimer disease have been generated, making use of CPP, fully reflecting the initial phases of sporadic forms of the disease; this novel model of Alzheimer disease can be further exploited for drug screening.

CPADS also produced new protocols for fast and specific kinase assays and analysis of protein complexes.

Finally, CPADS by exposing young scientists to a highly competitive academic-industrial network and to interdisciplinary / multidisciplinary and inter-sectorial research approaches contributed to the mobility and formation of a novel skilled generation of European young scientists.

Six fellows in total have been trained within the CPADS consortium: two of them have been recruited and four seconded. Fellows' mobility occurred not only across sectors, exposing them by secondments and short visiting periods to private and public research laboratories, but also across European countries (Italy, Switzerland, France). The differences in competences of CPADS partners also ensured an interdisciplinary training, ranging from basic science approach in brain diseases, to chemical-physical and computational approaches for peptide design-modelling-production, to development of innovative technical microscopy approaches to visualise protein complexes.

They have been exposed to cutting-edge technologies in the field of neurodegenerative disease research, trained on how to apply and expand novel technical approaches, but also exposed to complementary skills, such as project management and grant writing.

In addition, given the great involvement of laboratories participating to CPADS consortium, to European networks on neurodegenerative diseases, all fellows have been exposed to a stimulating international environment, through active participation to meetings and authorship in several peer reviewed scientific publications. Final results of CPADS have been presented at the International workshop 'The Synapse from physiology to pathology' (Stresa, 4 to 7 September 2012) and at the workshop 'Cell-permeable peptides: a tool to study neurodegeneration' (Milan, 21 February 2012).