The trouble with mice as behavioral models for Alzheimer’s – STAT – By Adam Rosenberg – Apr 2019
It is becoming increasingly obvious that rodents cannot accurately model human diseases, let alone human behaviors.
I’ve always doubted the findings of pain studies that use rodents because these animals cannot possibly model what is claimed to be a bio-psycho-social syndrome.
There’s been a lot of talk about overinvestment in interventions aimed at amyloid in the weeks since Biogen discontinued a late-stage study of aducanumab, an experimental therapy for Alzheimer’s disease.
Although much of the focus has been on the amyloid hypothesis at the heart of that work — and other failed treatments — I believe we are overlooking another key driver for numerous translational failures:
the overreliance on behavioral readouts from contrived transgenic rodent models to guide drug development for Alzheimer’s, Parkinson’s, and other neurologic diseases.
We need to find ways to move beyond this flawed paradigm.
In many areas of drug development, the most important preclinical metric is whether the compound showed signs of efficacy in an animal model, most often mice.
This makes sense for some diseases, and for certain forms of data. In movement disorders, for example, motor dysfunction is arguably conserved between mouse and human.
Similarly, if an agent heals a wound in a mouse, it’s reasonable to assume it may do the same in people.
But this breaks down when it comes to neurologic disorders that manifest themselves in distinctly human cognitive and functional behaviors.
And pain is exactly such a neurologic disorder, with distinctly human cognitive and functional behaviors. There’s no way to model human behavior in any other creature.
It is hard to argue with a straight face that assessing how speedily mice find their way around a maze appropriately models the complex interplay of cognitive, behavioral, and functional symptoms in human diseases such as Alzheimer’s or autism spectrum disorder.
What seems obvious to me is that the animal model paradigm is broken when it comes to complex neurologic diseases.
Let’s start with the highly inbred mouse models largely used for this kind of work. They lack the genetic diversity that may contribute to the severity and complexity of Alzheimer’s and other complex diseases in people.
This is arguably one reason why many preclinical studies in rodent models have failed to translate to humans.
A recent paper in the journal Neuron illustrates this point
it is impossible to model in mice all of the complex environmental inputs — everything from nutrition to education to exercise levels — that affect cognition, function, and behavior in people with neurologic disorders.
This is especially true for studies on opioids.
On the one hand, the “experts” insist chronic pain is a biopsychosocial issue, on the other hand, they assume studies on mice that lack all these psychological and sociological features can be applied to humans.
We’ll never know how many compounds were moved into the clinic based on questionable behavioral data. We’ll also never know how many otherwise promising compounds were shelved for failure to show “efficacy” in improving cognition in a flawed mouse model.
I am confident that the next decade of neuroscience research and development will be better than the last — as long as we don’t continue overinvesting in mechanisms that have proved fruitless and as long as we don’t continue to use behavioral data from contrived mouse models as a critical gatekeeper before clinical trials.
It’s time for the industry to evolve. We should start by taking a hard look at old paradigms.
Author: Adam Rosenberg is the president and chief executive officer of Rodin Therapeutics, a company based in Cambridge, Mass., aimed at discovering and developing therapies to enhance synaptic integrity to treat neurodegenerative, neurodevelopmental, and neuropsychiatric diseases