Abstract
In the last half-century, Parkinson’s disease (PD) has played a historical role in demonstrating our ability to translate preclinical scientific advances in pathology and pharmacology into highly effective clinical therapies. Yet, as highly efficacious symptomatic treatments were successfully developed and adopted in clinical practice, PD remained a progressive disease without a cure. In contrast with the success story of symptomatic therapies, the lack of translation of disease-modifying interventions effective in preclinical models into clinical success has continued to accumulate failures in the past two decades. The ability to stop, prevent or mitigate progression in PD remains the “holy grail” in PD science at the present time. The large number of high-quality disease modification clinical trials in the past two decades with its lessons learned, as well as the growing knowledge of PD molecular pathology should enable us to have a deeper understanding of the reasons for past failures and what we need to do to reach better outcomes. Periodic reviews and mini-reviews of the unsolved disease modification conundrum in PD are important, considering how this field is rapidly evolving along with our views and understanding of the possible explanations.
Highlights
Parkinson’s disease (PD) and movement disorder specialist clinicians frequently encounter patients inquiring about a “cure” for PD, or at least when it will be possible to slow down the progression of their disease
We review some possible contributors to the lack of translational success from preclinical to clinical therapeutic development for disease modification in PD, along with a brief (“mini”) assessment on the hopes of correcting or mitigating each of these obstacles
We propose that current standards of animal modeling and clinical testing of disease modification interventions in PD are two ends of a spectrum with regards to sample heterogeneity among individuals within study cohorts
Summary
PD and movement disorder specialist clinicians frequently encounter patients inquiring about a “cure” for PD, or at least when it will be possible to slow down the progression of their disease. Even though there were concerns raised about the true value of the MPTP model early on (Mari and BodisWollner, 1997), it became the gold standard testing ground for therapeutic developments, targeting (A) symptomatic and (B) disease modification treatments alike. At the time, those two conceptually different therapeutic goals were not necessarily seen as distinctly separate from each other from the preclinical modeling perspective as they are today. We review some possible contributors to the lack of translational success from preclinical to clinical therapeutic development for disease modification in PD, along with a brief (“mini”) assessment on the hopes of correcting or mitigating each of these obstacles.
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