TIRCON

Treat Iron-Related Childhood-Onset Neurodegeneration

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 Obiettivo del progetto (Objective)

Neurodegeneration with brain iron accumulation (NBIA) is a heterogeneous group of rare hereditary neurodegenerative disorders characterized by high levels of brain iron. The most common form is pantothenate kinase-associated neurodegeneration (PKAN). Classic PKAN and most other 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. This is especially unfortunate as both the iron accumulation in NBIA and the biochemical defect in PKAN are predicted to be amenable to drug-based treatment. Thus, the current absence of clinical trials is not due to lack of therapeutic options but to rarity of the disease, lack of patient registries and fragmentation of therapeutic research worldwide. For example, the iron-chelating drug deferiprone has been administered to PKAN patients on an individual basis or in pilot trials, both precluding firm conclusions about its efficacy. With TIRCON, we will address this urgent and unmet need for NBIA/PKAN therapy with an ambitious and highly collaborative plan that leverages worldwide expertise. 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, together with a European SME, we propose to pursue preclinical development of pantethine and its derivatives which have shown promising efficacy in a Drosophila PKAN model. To facilitate future research, we will develop a harmonized patient registry and biomaterial bank to allow for natural history studies and biomarker development, two critical needs in NBIA research. TIRCON partners, apart from their unique clinical and basic science expertise in NBIA, have longstanding experience in investigator-driven and industry-driven randomized clinical trials. Importantly, they have been closely collaborating in recent years.

Introduzione (Teaser)

A European consortium is working on new therapies for a group of rare neurodegenerative disorders called Neurodegeneration with Brain Iron Accumulation (NBIA).

Descrizione progetto (Article)

NBIA is a group of rare disorders characterised by high levels of iron accumulation in the brain. The most frequent form of NBIA is Pantothenate Kinase-Associated Neurodegeneration (PKAN). Symptoms in PKAN and most other NBIA forms present early in childhood, and the diseases progress to life-long disability and often to early death. As currently no cure is available to reverse or halt NBIA.

Iron accumulation and the enzyme defect in PKAN could in principle be amenable to drug-based treatment but scarcity and regional dispersal of patients have rendered research fragmented, precluding conduct of randomised clinical trials. At the core of the EU-funded http://www.tircon.eu/ (TIRCON) (Treat Iron-Related Childhood-Onset Neurodegeneration) project is a clinical phase 2/3 trial to test safety and efficacy of the iron-chelating drug deferiprone in a cohort of 90 PKAN patients from Europe and US, a drug that thus far is licensed only for other indications (thalassaemia). Despite of the rarity of PKAN with a prevalence of about 1 in 1 million, TIRCON has succeeded in fully recruiting this trial, which will be completed in autumn 2016.

In addition, TIRCON's now well established internationally harmonised patient registry comprises more than 230 patients, giving access to their pseudonymised data and biomaterial samples. This sample collection is used for genomic, proteomic, transcriptomic and metabolomic analyses to better understand causes and aetiology, and to identify biomarkers of NBIA.

The consortium is also active in evaluating the potency of other candidate therapies such as pantethine and its derivatives in pre-clinical animal models. Preliminary results show improvement of locomotor defects in NBIA animal models upon treatment with pantethine, which underscores its potential clinical use.

TIRCON infrastructure and tools as well as the highly collaborative new NBIA community will facilitate future research in NBIA, for example to identify biomarkers that can serve diagnosis, prognosis, and the monitoring of disease course and treatment effects. The interventional study at the core is anticipated to improve the therapeutic options for this progressive, highly disabling and life-threatening disease.