Project: Multicellular organoids: modeling, mechanisms and therapy development for C9ORF72-associated neurodegeneration

Acronym	ORGTHERAPY (Reference Number: JPND2019-466-041)
Project Topic	The delivery of therapeutic agents to the central nervous system (CNS) remains a major challenge. This is especially the case for the devastating disorders at the focus of the current proposal [amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)]. ALS is a fatal condition characterized by progressive muscle paralysis and other motor deficits. The most common genetic form of ALS and FTD is caused by expansion of a hexanucleotide repeat (G4C2) in the non-coding region of chromosome 9 open reading frame 72 (C9ORF72). While significant discoveries have recently been made in the genetics of ALS, patients still have no real therapeutic treatments. The lack of any cure for ALS-linked C9ORF72 is attributable primarily to four challenges: (i) Poor understanding of the molecular pathogenesis of motor neuron degeneration and the underlying causes of the variability that characterises the patient population; (ii) Lack of reliable animal models and/or model system mimicking the multicellular and multi-mechanism complexity of the human disease; (iii) Delivery of therapeutically attractive molecules has been hampered by inefficient delivery methods including factors like the blood-brain barrier (BBB); (iv) Ineffective targeting of therapeutic agents specifically to the diseased CNS site and/or cell type. The economic burden of care for patients with ALS continues to significantly rise in Europe. Thus, research efforts aimed at understanding how mutations in ALS causative genes affect various cell types and pathways, thus leading to motor neuron degeneration are of the utmost importance to enable therapeutic development for these disorders. The limitations associated with existing C9orf72 animal models can be overcome by using specific patient induced pluripotent stem cells (iPSC)- derived 3D models. Thus, organoids provide unique opportunities for personalized medicine as a system for the development of pharmacological or tailored gene therapies for C9ORF72-linked neurodegeneration. Here, we assembled a multidisciplinary research team with complimentary expertise to examine strategies how to overcome some of these challenges. The overall aims of our research programme are: (1) Generate 3D in vitro multicellular organoids models from iPSCs derived from healthy and patients with C9ORF72 ALS/FTD; (2) Fully characterise the newly generated models using established assays in the consortium (e.g. molecular markers and electrophysiology); (3) Explore mechanistic pathways in particular pro-inflammatory, anti-oxidant and DNA damage pathways; (4) Drug and gene based therapeutic screening in collaboration with AstraZeneca.
Network	JPCOFUND2
Call	PERSONALISED MEDICINE FOR NEURODEGENERATIVE DISEASES

Project partner

Number	Name	Role	Country
1	University of Sheffield	Coordinator	United Kingdom
2	Istanbul Medipol University	Partner	Türkiye
3	King's College London	Partner	United Kingdom
4	Uppsala University	Partner	Sweden
5	University of Eastern Finland	Partner	Finland
6	Elvesys	Partner	France