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

Abstract

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.

Keywords: Huntington's disease; neurodegeneration; point of no return; spinocerebellar ataxia type 1; therapy.

Figure 1

Points of no-recovery in neurodegenerative disease. With increasing age and disease duration neuronal pathology progressively worsens, reaching a point where neuronal death ensues (A). During this period there is a decline in neurological status (B) and alterations in gene expression and physiology (C). Changes in gene expression typically fall into two categories, those associated with disease progression – solid triangle – and those largely reflecting neuronal loss – hatched box. Changes in A-C impact ability of therapeutic approaches to impact disease progression and induce recovery (D). During early phase of disease there is a period when mechanistic therapeutic approaches are effective, but with diminishing effect with age – green triangle. With neuronal death a point of no-return is reached – red bar. It is proposed that an initial point of no-recovery occurs prior to neuronal death – hatched red bar