The report, recently published by PLOS ONE, includes a review of more than 500 animal and human studies of Parkinson's disease published over the last 40 years.
Caroline Zeiss, professor of comparative medicine at Yale, told us that while human trials for interventions that slow the progression of neurodegenerative disease have a high failure rate, animal studies for the same intervention are usually promising.
With this in mind, the researchers sought to analyze to what extent study design issues affect the translation of animal research to the clinic.
“The trend seen most commonly in these animal studies was that the intervention was given prior to, or soon after Parkinson’s disease (PD) was induced, unlike human Parkinson’s patients,” explained Zeiss.
The researchers also found preferential use of young male animals, particularly in mice, as well as use of only one time point to assess outcome and biomarkers with no validated relationship to clinical outcome to determine improvement.
“Additionally, researchers relied heavily on acute and non-progressive toxic models of PD,” explained Zeiss. “These trends were less prevalent, but also less crucial, in studies for symptomatic therapies, because the intent of these was to relieve symptoms with each dose, not slow the disease.”
Designing more translationally relevant animal studies
Specifically, Zeiss explained that in order to demonstrate neuroprotection of potential value to human patients, the intervention must demonstrate “a reduced trajectory of severity of already established disease over time in animals.”
This requires study designs that model the progressive nature and relatively late intervention characteristic of PD in humans, she said, as well as studies that anchor mechanistic and neuropathologic data to longitudinal clinical outcomes.
“Additionally, because animal models tend to be reductionistic, individual models cannot replicate the molecular complexity of human Parkinson’s disease,” Zeiss added. As such, an intervention that is effective across different experimental systems and species would have greater potential for translation.
“Mice in particular are used primarily to demonstrate that a mechanism has potential therapeutic value, with less emphasis placed on study design aspects that are directed towards confirmation of translational potential,” Zeiss said.
“While proof of concept studies may reveal important insights, they are usually not generalizable to more complex human disease. Use of more translationally relevant study designs may reduce the number of promising outcomes in animals.”
Guidelines and implementation
Various measures to improve animal study design and reporting have been proposed, such as through the ARRIVE guidelines, which could improve the reproducibility of individual animal studies if adopted.
“However, without adoption of measures that also improve generalizability of animal studies to humans, they may improve reproducibility within a confined ecosystem of animal studies, and do little to improve translation to humans,” Zeiss said.
Ultimately, she explained, “We need to design more translationally relevant animal studies, and we need to look at the evidence of multiple studies together before human trials are initiated for a given intervention.”