Why Do Some Neurological-Focused Drugs Work in Mice and Not Humans?


Preclinical data that show successful outcomes in mice often generate excitement in the news, but when it comes to treating humans with the same condition, typically neurological disorders like Alzheimer’s disease or glioblastoma, oftentimes the drugs do not work.

Of 100 neuropsychiatric drugs tested on mouse models, only nine made it all the way through the clinic and were approved by regulatory agencies, according to STAT News. The failings of these drugs marked the lowest rates of all disease categories, according to the report. Now, scientists have a greater understanding of why that is so. In a new article published in Nature, and first reported by STAT, the researchers found that differences at the cellular level between people and mice play an important role. Mice and other rodents are often used as animal models because their genetic, biological and behavior characteristics closely resemble those of humans. In early research, many symptoms of various diseases that affect humans can be replicated in mice and then treated. However, the latest research shows a distinct difference in the types of cells in the cerebral cortex of humans and mice. In the Nature article, the researchers said that “found extensive differences between homologous human and mouse cell types, including marked alterations in proportions, laminar distributions, gene expression and morphology.” And those differences are distinct enough for the researchers to stress the “importance of directly studying (the) human brain.”

As STAT noted in its story, for this research, the scientists did not sort the brain cells of mice and men by shape and location, which has been common, but rather through which genes those cells used.

“That makes neurons and circuits connecting brain regions, which were long thought to be essentially identical in mice and people, different in a fundamental way. And it could explain the abysmal record of drug development for neuropsychiatric diseases including schizophrenia, depression, bipolar disorder, and autism,” STAT said in its report.

Ed Lein, a neurobiologist at the Allen Institute for Brain Science in Seattle and the lead author of the study, told STAT that the drugs being developed for diseases like Alzheimer’s act on receptors and other molecules. The new research points out that the reason many of these drugs fail is because the neurotransmitter receptor being targeted may not actually be in the same cells in humans as it is in mice. If that’s the case, then Lein clearly points out that the investigative drug will “hit the wrong circuit” and not have the same effect in humans as it does in mice.

With the new information in hand from Lein and his team, neurobiologists working on Alzheimer’s and other brain-related diseases are hopeful that the diseases that have stymied the drug developers will soon have some treatment options. Eric Nestler of the Icahn School of Medicine at Mount Sinai, neurobiologist not involved in the study, told STAT that research from Lein’s team called provides a “useful roadmap” for researchers to develop drugs. Armed with the latest information, scientists will be able to “make better use of mouse models” when developing treatments, Nestler said.

While the data offers some hope in future drug developments, it is as of yet unknown how the pharma industry will react, particularly companies that have invested hundreds of millions of dollars into developing an Alzheimer’s treatment, only to have it fail in late-stage trials, such as Biogen and Eli Lilly. While those companies, among others, maintain an interest in developing a treatment, time will tell in how the Lein-lead study makes a difference in drug development.

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