Clinical tests of neurotrophic factors for human neurodegenerative diseases, part 2: Where do we stand and where must we go next?

The therapeutic potential of neurotrophic factors has been recognized for decades, with clinical trials in human neurodegenerative diseases extending back at least 25years. While improvements in clinical dosing paradigms have reduced the side effects commonly seen in the earlier trials, efficacy has remained a serious disappointment (reviewed in Bartus and Johnson, 2016). This lengthy clinical effort stands in contrast to robust effects consistently achieved from different neurotrophic factors in a variety of animal models of neurodegeneration. This review discusses the prevailing assumption and supporting data that the major reason for the disappointing efficacy of past clinical trials is related to suboptimal dosing methods. It is concluded that while further improvements in dosing parameters might be useful, a much greater problem centers around a number of specific morphologic and functional changes in neurons in human neurodegenerative disease that mitigate the ability of neurotrophic factors to exert their effects. Moreover, the biological substrate which neurotrophic factors depend upon to exert their effects continues to erode as time progresses, due to the progressive nature of these diseases. For this reason, most of the empirically-supported reasons contributing to the weak neurotrophic responses in human patients can be mitigated by enrolling less severely advanced cases. It is further concluded that recent clinical trials of neurotrophic factors have generated important evidence that shifts risk: benefit assessments to support enrolling earlier-stage patients. While the Alzheimer's field has begun to shift attention toward much earlier-stage (even prodromal) patients in trials intended to modify disease progression, other neurodegenerative diseases (e.g., Parkinson's, ALS and possibly HD) must now consider similar changes in approach.