European network and registry for homocystinurias and methylation defects (E-HOD)

Main partner: VU University medical center, part of Stichting (VUmc, the Netherlands)

The project is focused to:

1. Describe the natural history and outcome of homocystinurias and methylation defects including: Long-term organ-specific complications; acute metabolic crisis; survival rate; genotype /phenotype correlation; differences in the disease course relating to the genetic background / ethnic origin / gender effects;
2. Describe and evaluate the efficacy and safety of current treatment strategies;
3. Compare the diagnosis, treatment and management of affected individuals in different European countries, including the newborn screening programmes;
4. Identify the major impact of a rare inherited disease on quality of life, school education, professional career and social life of patients and their families.

The overall intended impact is to improve access to rapid diagnosis and optimal care for patients with homocystinurias, methylation defects and folate defects.

European registry and network for Intoxication type Metabolic Diseases (E-IMD)

Main partner: Universitätsklinikum Heidelberg (Germany)

The overall aim of the European registry and network for Intoxication type Metabolic Diseases (E-IMD) is to promote health for individuals affected with rare organic acidurias (OADs) or urea cycle defects (UCDs). E-IMD has two specific objectives:

1. to establish a European patient registry describing the disease course, epidemiology, diagnostic and therapeutic strategies for OADs and UCDs and to provide information to national and EU healthcare authorities. Anonymised data collection via a web-based password-protected EU registry will be based on routine follow-up parameters in 15 EU countries.
2. to provide European evidence-based consensus care protocols for patients with OADs and UCDs.

Based on the largest available collection of patient data and a systematic literature search, a European consensus group will describe the best evidence available for the diagnosis and treatment. Consensus care protocols will be translated into official EU languages, provided via the E-IMD website and serve as a template for national guidelines and patient brochures.

An EU rare diseases registry for Niemann-Pick Disease type A, B and C (NPDR)

Main partner: University Hospitals Birmingham NHS Foundation Trust (UHB, Great Britain)

The general objective of this project is to support accurate and timely diagnosis, treatment, and research for Niemann-Pick diseases (NPD) type A, B & C.

An EU registry for NPD, containing clinical, genetic diagnostic and outcome data, will be implemented in order to:

1. establish the natural history of the 3 diseases (their characteristics, management and outcomes);
2. assess clinical effectiveness of management and quality of care;
3. provide an inventory of patients for recruitment to interventional studies;
4. to establish genotype-phenotype correlations.

The overall intended impact is to provide equal access to biochemical and genetic testing, education of health professionals, and empowerment of patients.

Artificial Cells for Enzyme Replacement Therapy for Phenylketonuria (AC FOR PKU TREATMENT)

Main Partner: Aarhus Universitet (Denmark)

This research project is aimed to further develop the sub-compartmentalized assembly named capsosomes as an oral-delivered artificial cell for enzyme replacement therapy with the aim to provide a solution for phenylketonuria. In particular,  the preservation of the PAL activity for oral administration  synthesize thiol-modified PDA (PDASH) with the aim to obtain biodegradable capsosomes at intestine physiological concentrations of glutathione (GSH).

Augmenting PBGD expression in the liver as a Novel Gene therapy for Acute Intermittent Porphyria (AIPGENE)

Main Partner: Fundacion Para La Investigacion Medica Aplicada (FIMA, Spain)

Acute intermittent porphyria (AIP) is a rare genetic disease in which mutations in the porphobilinogen deaminase (PBGD) gene produce insufficient activity of a protein necessary for heme synthesis. This leads to an accumulation of toxic intermediates resulting in a wide variety of problems including neurological disorders. The currently available therapies do not prevent the symptoms or consequences of acute porphyric attacks. The only curative therapy is liver transplantation and thus, new curative options are clearly needed. In 2009, the European Medicines Agency granted Orphan Drug Designation to AAV5-AAT-PBGD for the treatment of AIP. AAV is a replication-incompetent virus that acts by delivering the PBGD expression cassette directly into hepatocytes. The project will be performed in three different phases:1) the development of a GMP-compliant process to produce sufficient AAV5-AAT-PBGD for clinical trials; 2) the investigation of safety and efficacy of AAV5-AAT-PBGD in a dose escalation clinical phase I/II trial.

A Treatment-Oriented Research Project of NCL Disorders as a Major Cause of Dementia in Childhood (DEM-CHILD)

Main Partner:  Universitaetsklinikum Hamburg-Eppendorf  (UKE, Germany)

The neuronal ceroid lipofuscinoses (NCLs) are neurodegenerative diseases characterized by dementia, blindness, epilepsy and physical decline leading to an early death of the patients. To date, eight NCL genes have been characterised. There is evidence suggesting that further gene loci remain to be identified. NCLs are under-diagnosed in many countries around the worldand no cure is currently available. The DEM-CHILD project will combine the expertise of (i) recognized European research teams with (ii) high-technology SMEs, and will (iii) collaborate with Indian experts to develop innovative cost- and time-effective testing and screening methods for all NCLs. The project also aims to collect the worlds largest, clinically and genetically best characterised set of NCL patients; to identify novel biomarkers and modifiers of NCL to support the development of innovative therapies; to use and compare two complementary therapeutic strategies in eye and brain of mouse models.

Therapies for inborn errors of metabolism (IEMTX)

Main partner: Telethon (Italy)

This project aims to investigate the efficacy and the therapeutic potential of several FDA-approved drugs which share with phenylbutyrate a similar mode of action and are able to  increase the enzymatic activity of both branched chain ketoacid dehydrogenase complex (BCKDC) and pyruvate dehydrogenase complex (PDHC). PDHC deficient neurons and maple syrup urine disease (MSUD)  hepatocytes from induced pluripotent stem cells (iPSCs) derived from patients fibroblasts are planned to be developed. Drug response in these disease-relevant cell types will better predict clinical response of patients. We will investigate altered metabolic pathways in PDHC deficient neurons and MSUD hepatocytes to search for effective drugs by an innovative systems biology approach. In summary, the results of the proposed study have the potential to provide novel and effective treatments for MSUD and PDHC deficiency.

Investigation of metabolic processes underlying brain myelination defects using magnetic resonance spectroscopy of oligodendrocyte extracts (JIMPYSPEC)

Main partner:  University Louis Pasteur (ULP, France)

The proposed research aim is to investigate metabolic processes underlying myelination defects in the CNS. Alterations in the processing of Proteolipid protein (PLP) are a major cause in inherited diseases of CNS myelin. For instance, the Pelizaeus Merzbacher disease is a disorder of the central nervous myelination, caused in most cases by mutations involving the PLP gene.

Therapeutic challenge in Leukodystrophies: Translational and ethical research towards clinical trials (LEUKOTREAT)

Main Partner: Universite D’auvergne (UdA), Clermont-Ferrand 1 (France)

The development of therapeutic approaches for myelin repair and neuro-protection constitutes the main objective of the LeukoTreat project.  The global aim is to promote the development of therapeutic strategies for the largest number of Leukodystrophies (LDs)  affected patients and further applications to more common white matter disorders and finally neurodegenerative diseases. The LeukoTreat project is based on 5 complementary approaches consisting in: (i) collecting information on the epidemiology, the natural history, the genotype/phenotype correlation of LDs for at least 500 patients; (ii) validating/identifying biomarkers for therapeutic decisions/follow up to isolate new therapeutic targets; (iii) developing pharmacological strategies with the ultimate objective to launch at least 4 pharmacological clinical trials during 5 years following the project; (iv) developing innovative gene and cell therapies with the ultimate objective to launch at least 3 clinical trials during the next 5 years; (v) tackling ethical impacts of the proposed therapeutic challenges by integrating the participation of patients driven by a well-experienced research team strongly skilled in ethics.

Synthesis of mono-dithiolene molybdenum complexes and their evaluation as potential drugs for the treatment of human isolated sulfite oxidase deficiency (MOCOMODELS)

Main partner: Ernst-Moritz-Arndt-Universität Greifswald (Germany)

Isolated sulfite oxidase deficiency (iSOD)  diseases are two rare but usually fatal diseases are caused by a failure at different levels of the multistep biosynthetic generation of the three human molybdenum dependent enzymes involved in metabolic processes. The proposed project is aimed at synthesising molybdenum complexes that mimic the natural molybdenum cofactor of the respective enzymes, testing their potential for incorporation into the biotechnologically generated apo-enzyme and evaluating the activity of the resulting semi-synthetic enzymes thereby assessing their suitability as future iSOD treatments. This work will have impact on the way iSOD and MocoD patients will be treated in the future and deepen the understanding of fundamentally important chemical, structural and catalytic aspects of the Moco dependent enzymes.

Developing therapies for Nitric Oxide (NO) related neurodegeneration (NO-BRAINER)

Main partner: Weizmann Institute Of Science (WIS, Israel)

Approaches targeted at modulating NO synthase (NOS) activities have not successfully translated into therapyIn humans, argininosuccinic acid lyase  deficiency (ASLD) causes argininosuccinic aciduria, the second most common urea cycle disorder. We recently demonstrated a new structural requirement of argininosuccinic acid lyase (ASL)  for maintenance of a NO synthetic complex necessary for generation of NO from intracellular and extracellular sources of arginine. Regulating ASL would allow us to characterize the cellular and molecular mechanisms underlying the NO flux at normal and pathological conditions, for therapeutic applications. As a proof of concept, we will start by dissecting NO metabolism in the central nervous system at homeostasis and in acute and chronic brain injury. Our results will provide a novel approach for the study of other NO related disorders, with therapeutic application.

Quantitative Large Scale Proteomics of Lysosomal Storage Disease (STORAGE PROTEOMICS)

Main Partner: Universitaetsklinikum Bonn (UKB, Germany)

To gain insight into Lysosomal Storage Disease (LSD) mechanisms the project investigates cellular proteomic alterations sequentially induced by increasing lysosomal storage through in vivo and in vitro models and proteomic techniques. Alterations in protein expression and phosphorylation will be identified, grouped and analyzed for up- and downstream interaction partners as well as biological processes they are involved in. These data will allow describing cellular consequences of lysosomal storage in a so far unprecedented way, will allow generating new working hypotheses, and may provide the basis for the identification of new therapeutic targets.

Treat Iron-Related Childhood-Onset Neurodegeneration (TIRCON)

Main Partner: Ludwig-Maximilians-Universitaet (LMU, Germany)

Pantothenate kinase-associated neurodegeneration (PKAN) and most other neurodegeneration with brain iron accumulation (NBIA) cases are characterised by early childhood onset and rapid progression. Currently, there is no proven therapy to halt or reverse PKAN or any other NBIA. We propose a large investigator-driven randomized clinical trial of deferiprone in PKAN, bringing together leading centres and patient advocacy groups from Europe and the US to reach the required patient cohort size.  In addition, the following steps are planned: a preclinical development of pantethine and its derivatives which have shown promising efficacy in a Drosophila PKAN model; a development of a harmonized patient registry and biomaterial bank to allow for natural history studies and biomarker development.

Early treated patients with PKU: Exploring the association between measures of metabolic control, cognitive performance and neurological health (TREPAPHEN)

Main partner: Aston University (United Kingdom)

Phenylketonuria (PKU) is an inherited metabolic disease which, if left untreated, results in severe mental retardation. The research team for TREPAPHEN is treating one of the largest cohorts of PKU patients in the UK with records of blood levels of Phe since infancy. TREPAPHEN will carry out an in-depth assessment of the cognitive performance of these patients in critical target areas and relate it not only to adult blood levels of Phe but also to measures of brain functions at different levels (structural, neurological and metabolic).