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Diminishing return for mechanistic therapeutics with neurodegenerative disease duration?: There may be a point in the course of a neurodegenerative condition where therapeutics targeting disease-causing mechanisms are futile.

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Rubinsztein, David C 
Orr, Harry T 


The conventional approach to developing disease-modifying treatments for neurodegenerative conditions has been to identify drivers of pathology and inhibit such pathways. Here we discuss the possibility that the efficacy of such approaches may be increasingly attenuated as disease progresses. This is based on experiments using mouse models of spinocerebellar ataxia type 1 and Huntington's disease (HD), where expression of the dominantly acting mutations could be switched off, as well as studies in human HD, which suggest that the primary genetic driver of age-of-onset of disease is a much weaker determinant of disease progression in affected individuals. The idea that one may approach a point in the disease course where such rational therapeutic strategies based on targets which determine onset of disease have minimal efficacy, suggests that one needs to consider other approaches to therapies and clinical trial design, including initiation of therapies in presymptomatic individuals.



Huntington's disease, neurodegeneration, point of no return, spinocerebellar ataxia type 1, therapy, Animals, Disease Models, Animal, Disease Progression, Huntington Disease, Mice, Prognosis, Spinocerebellar Ataxias

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Wellcome Trust (095317/Z/11/Z)
Cambridge University Hospitals NHS Foundation Trust (CUH) (unknown)
European Commission (305121)
Wellcome Trust (100140/Z/12/Z)
DCR is grateful for funding from the Tau consortium, Alzheimer’s Research UK (DCR), Wellcome Trust (Principal Research Fellowship to DCR, 095317/Z/11/Z), a Wellcome Trust Strategic Grant to Cambridge Institute for Medical Research(100140/Z/12/Z), NIHR Biomedical Research Unit in Dementia at Addenbrooke’s Hospital and the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement number 2012-305121 “Integrated European -omics research project for diagnosis and therapy in rare neuromuscular and neurodegenerative diseases (NEURO-MICS). HTO is appreciative for research support from the NINDS/NIH, grants R37NS022920 and RO1NS045667 and grants from the National Ataxia Foundation and the Bob Allison Ataxia Research Center.