Abstract
Despite major advances in our understanding of the initiating factors that trigger many neurodegenerative disorders, to date, no novel disease-modifying therapies have been shown to provide significant benefit for patients who suffer from these devastating disorders. As most neurodegenerative disorders are late-onset, slowly progressive, and appear to have long relatively asymptomatic prodromal phases, it is possible that therapies optimally targeting the triggers of these disorders may have limited benefit when treatment is initiated in the symptomatic patient. Such therapies may work in the prodromal phase, or when given prophylactically, but in the symptomatic patient there simply may be too much damage to the neuronal networks to restore functionality by reducing or even eliminating the primary stressor. As functional neuronal demise and overt neuronal death are almost certainly the key factors that mediate the functional impairment, it is clear that preventing neuronal death and dysfunction will have a huge clinical benefit. Unfortunately, we lack a detailed understanding of neuronal death pathways in almost all neurodegenerative disorders. To rationally develop new disease modifying therapies that target steps in the degenerative cascade downstream of the disease trigger will require a number of factors. First, we need to refocus our basic research efforts on identifying the precise steps in the pathological cascade that lead to neuronal death in each neurodegenerative disease and, if possible, determine the relative placement of those events within a potentially very complex cascade. Second, we will need to determine which of these steps are potentially targetable. Finally, we will need to develop novel therapies that interfere with these steps and demonstrate that such therapies alone, or in combination with therapies that target the trigger of these devastating diseases, have clinical benefit.
Highlights
Over the last two decades there has been enormous progress with respect to understanding the initiating factors that trigger complex cascades that result in various neurodegenerative disorders [1,2,3]
At least with respect to anti-Aβ therapies, that the numbers of therapeutic approaches are sufficient to determine whether such strategies will be efficacious in humans with Alzheimer' disease (AD), it would seem that there should be a renewed focus by academics with respect to identifying the downstream pathways that mediate neuronal death
We do know the trigger, or at least in most diseases there is a reasonable consensus that we know enough about the trigger to develop strategies to target it therapeutically (Appendix 1)
Summary
Over the last two decades there has been enormous progress with respect to understanding the initiating factors that trigger complex cascades that result in various neurodegenerative disorders [1,2,3]. At least with respect to anti-Aβ therapies, that the numbers of therapeutic approaches are sufficient to determine whether such strategies will be efficacious in humans with AD, it would seem that there should be a renewed focus by academics with respect to identifying the downstream pathways that mediate neuronal death Such studies will almost certainly identify novel targets that can be moved towards the clinic. One possible way to leverage such therapeutic development is to demonstrate that the pathway targeted http://www.molecularneurodegeneration.com/content/4/1/8 may play a role in the rare condition but in a common condition such as PD or AD This is unlikely to work for therapies targeting a trigger of the disease, but could work if dysfunction of a critical downstream pathway drives neuronal dysfunction and death in multiple diseases. It is the intent of this series to provide a "road map" for the field to refocus on the question of the pathways that conspire to kill neurons in various neurodegenerative diseases, and hopefully galvanize a new era of therapeutic development that will result in novel disease modifying therapies for patients suffering form these devastating disorders (Appendix 2)
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