European Integrated Project on Spinocerebellar Ataxias Pathogenesis, genetics, animal models and therapy European Integrated Project on Spinocerebellar Ataxias Pathogenesis, genetics, animal models and therapy Funded by European Commission, Budget: 9,45 Mio Euro

SCA as an „Orphan disease“ Frequency 1 : Highly heterogenous NO cure, patients die after years of suffering Autosomal dominantly inherited, therefore „family disease“ Main symptom: disturbance of movement coordination Frequency 1 : Highly heterogenous NO cure, patients die after years of suffering Autosomal dominantly inherited, therefore „family disease“ Main symptom: disturbance of movement coordination

Frequency of genetically defined SCA subtypes in Europe

Argument for an IP on SCA Effort of an IP needed to generate the very basis to be able to tackle the lack of avaibility of effective treatment 1. Clinical tools and knowledge 2. Genetic tools and knowledge 3. Elucidation of pathogenic pathways Effort of an IP needed to generate the very basis to be able to tackle the lack of avaibility of effective treatment 1. Clinical tools and knowledge 2. Genetic tools and knowledge 3. Elucidation of pathogenic pathways

Clinical tools and knowledge Resources of the clinical centres of 9 European countries + 2 subcontracted centres 1. Clinical tools and knowledge 2. Genetic tools and knowledge 3. Elucidation of pathogenic pathways

Clinical tools and knowledge Resources of the clinical centres of 9 European countries + 2 subcontracted centres Information EUROSCA-Register: central pooling of patient data of Europe (more than 1400 entries to date) Standardized examination Design and validation of clinical Rating Scale (SARA): standardized assessment and rating of SCA (167 patients in validation trial) Progression Natural history study (collectives with 100 patients for SCA1,2,3,6 over 4 years) Marker Progression marker (MRI and electrophysiology) Resources of the clinical centres of 9 European countries + 2 subcontracted centres Information EUROSCA-Register: central pooling of patient data of Europe (more than 1400 entries to date) Standardized examination Design and validation of clinical Rating Scale (SARA): standardized assessment and rating of SCA (167 patients in validation trial) Progression Natural history study (collectives with 100 patients for SCA1,2,3,6 over 4 years) Marker Progression marker (MRI and electrophysiology) 1. Clinical tools and knowledge 2. Genetic tools and knowledge 3. Elucidation of pathogenic pathways

Clinical tools and knowledge Resources of the clinical centres of 9 European countries + 2 subcontracted centres Result of EUROSCA after 5 years: Rready-to-use tools and knowledge for interventional trials Resources of the clinical centres of 9 European countries + 2 subcontracted centres Result of EUROSCA after 5 years: Rready-to-use tools and knowledge for interventional trials 1. Clinical tools and knowledge 2. Genetic tools and knowledge 3. Elucidation of pathogenic pathways

Clinical tools and knowledge 1. Clinical tools and knowledge 2. Genetic tools and knowledge 3. Elucidation of pathogenic pathways The first SARA validation trial allowed to determine which SARA score corresponded to the ataxia stages. Using the knowledge of a retrospective study we estimated that SCA3 patients deteriorate by 2.3 points per year with a standard variation of 1.5 to 2.1 points. On the basis of these data we were able to calculate the number of patients required to detect an effect of a disease-slowing treatment in a two-year trial with 90% power. Redu. (%)SDnumberSDnumber x 18 2 x 49 2 x x x 10 2 x 25 2 x 55 2 x 216

Genetic tools and knowledge Resources of four clinical-genetic centres and all clinical centres Causing genes Linkage screen: c entral pooling of DNA samples of large families with patients of unknown SCAs (about 20% of known patients), Objective: identification of novel loci and genes. Modifiing genes Modifier screen: l arge number of DNA samples of patients of one SCA subtype needed, Objective: identifiction of variations in the genome which have influence on age of onset and/or progression. Resources of four clinical-genetic centres and all clinical centres Causing genes Linkage screen: c entral pooling of DNA samples of large families with patients of unknown SCAs (about 20% of known patients), Objective: identification of novel loci and genes. Modifiing genes Modifier screen: l arge number of DNA samples of patients of one SCA subtype needed, Objective: identifiction of variations in the genome which have influence on age of onset and/or progression. 1. Clinical tools and knowledge 2. Genetic tools and knowledge 3. Elucidation of pathogenic pathways

Elucidation of pathogenic pathways Resources of 9 research centres and 5 core facilities Common pathways Most frequent SCAs (SCA1,2,3,6,7,17) are member of Trinucleotid repeat diseases. Resources of 9 research centres and 5 core facilities Common pathways Most frequent SCAs (SCA1,2,3,6,7,17) are member of Trinucleotid repeat diseases. 1. Clinical tools and knowledge 2. Genetic tools and knowledge 3. Elucidation of pathogenic pathways CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG

Elucidation of pathogenic pathways Resources of 9 research centres and 5 core facilities Common pathways Most frequent SCAs (SCA1,2,3,6,7,17) are member of Trinucleotid repeat diseases. Resources of 9 research centres and 5 core facilities Common pathways Most frequent SCAs (SCA1,2,3,6,7,17) are member of Trinucleotid repeat diseases. 1. Clinical tools and knowledge 2. Genetic tools and knowledge 3. Elucidation of pathogenic pathways Animal models Mouse and drosophila models of these (most frequent) SCAs Core facilities Cutting-edge technological service provider which 1. are experts in SCA, 2. cover the pathogenic mechanisms as comprehensive as possible.

Likely situation after EUROSCA Clinic: Ready-to-use tools and expert knowledge for interventional trial Patient collectives that may meet the requirements of interventional trials Research: Promising substances NEEDED: MONEY FOR CLINICAL TRIALS Clinic: Ready-to-use tools and expert knowledge for interventional trial Patient collectives that may meet the requirements of interventional trials Research: Promising substances NEEDED: MONEY FOR CLINICAL TRIALS

EUROSCA people