Why age (and timing) really matters in developing drugs for neurodegenerative disease

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Date: Sept. 2011
From: Therapy(Vol. 8, Issue 5)
Publisher: Future Medicine Ltd.
Document Type: Editorial
Length: 1,845 words
Lexile Measure: 1300L

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Author(s): Dave Morgan [[dagger]] 1 , Amanda G Smith 2



Alzheimer'âs; animal model; clinical trial; drug development

Diseases of the aging nervous system are continuing to afflict a larger and larger portion of the population. Diseases such as stroke, Alzheimer'âs and Parkinson'âs impact nearly 10 million Americans [1-3] . These sizeable markets have attracted significant interest from the pharmaceutical industry and a tremendous amount of effort and money have been expended seeking medications to relieve the suffering. However, the track record in moving drugs from successful preclinical testing to effectiveness in human trials has been poor. In stroke and traumatic brain injury, a wide range of NMDA receptor antagonists have been remarkably successful in minimizing secondary damage in rodent models, yet had no impact in a series of human clinical studies [4] . In Alzheimer'âs, anti-inflammatory drugs and anti-amyloid approaches have found considerable success in mouse models of select aspects of the disease, yet, to date, none have slowed progression of disease in mild-to-moderate patient populations [5-7] . These consistent failures have led one of us (DM) to facetiously argue that the most efficacious treatment for human neurodegenerative disorders would be conversion to mice!

However, there are a couple of important considerations that have not been accounted for in most of the drug development literature. One is the impact of age on these studies. For all of the neurodegenerative conditions, the afflicted are those of advanced years with typically one or more comorbidities. These patients also experience varying degrees of polypharmacy to treat both existing and potential conditions (e.g., statins for heart disease risk) leading to unpredictable interactions with the tested agent. Yet, rodent studies of human conditions are almost always performed on very young animals. These younger animals are known to have remarkable reserve capacity in most organ systems compared with their aged counterparts [8] . As a result, removing the pathologic insult often leads to spontaneous restoration of functional capacity due to capacious residual plasticity. However, an aged human with neurodegenerative disease typically accumulates considerable damage before symptoms emerge and the minimal residual reserve capacity is insufficient to effect a functional restoration. Thus, even when the agent is on target and impacts the pathology, the trials may fail as there is no detectable clinical improvement.

A second consideration is the timing of the drug administration relative to the stage of the disease. In rodent models, agents are administered very early in the disease process. For stroke, some drugs can be applied before stroke is induced or very shortly thereafter. In mouse models of amyloid deposition for Alzheimer'âs, animals are often treated when the first deposits begin to appear in the brain (usually 3-6 months of age in an animal with a 24-month mean lifespan). There are now over 100 agents reported to 'cure'â amyloid-depositing...

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Gale Document Number: GALE|A268609812