In the critically-acclaimed film Away From Her, Fiona, a woman descending into the confusion of Alzheimer’s disease, tells her husband, “I think I may be beginning to disappear.” She is not alone in that feeling. More than 5 million people in the United States are diagnosed with Alzheimer’s, and the few drugs currently on the market treat only the symptoms of this devastating neurodegenerative disorder. New work in stem cell technologies, however, may change the way we treat Alzheimer’s, offering a new and personalized approach to identify and test medications that might prevent or reverse the progression of the disease.
The trouble with Alzheimer’s drugs
Today, Alzheimer’s is most commonly treated with cholinesterase inhibitors. But these drugs are only prescribed after significant damage has already occurred. They don’t work for all patients and, when they do, the effects last only six months to a year. Lawrence Goldstein, director of the University of California San Diego’s Stem Cell Program, says there is good reason for that.
“The drugs on the market don’t actually treat the underlying cause of Alzheimer’s,” he says. “They give symptomatic relief—and only temporarily. Drugs like cholinesterase inhibitors prolong the lifetime of acetylcholine in the cortex so you get some extra cortical stimulation but they don’t change the loss of synapses, the death of neurons or any of the core pathologies. They are treating the symptoms, not the disease.”
The difficulty in developing effective drugs for treating Alzheimer’s is that those drugs were developed to treat the end stage phenotype, says Roberta Diaz Brinton, the director of the Center for Scientific Translation at the University of Southern California. “We now know that Alzheimer’s pathology develops over about 20 years and that there are multiple trajectories and etiologies that result in that final end stage pathology,” she says. “But when we started drug development, we only knew about those end-stage plaques and tangles and that’s the kind of damage the drugs we developed were trying to limit.”
Furthermore, many of the current classes of drugs have been tested only on animals. “We’ve worked on animal models for years. And while animal models tell us important things, they don’t tell us everything,” he says. “And those differences may be very important to our ability to develop therapies. The details are important.”
Creating the human model
Yadong Huang, an investigator at University of California San Francisco’s Gladstone Institute, also found his work on potential therapies hindered by the lack of a working human model of the disease. Those concerns had him extend his lab’s work on Alzheimer’s pathogenesis to include some stem cell work. In the July 6 issue of Cell Stem Cell, Huang and his colleagues demonstrated that they could transform human skin cells into neurons using only a single genetic factor, Sox2, an important regulator gene. What’s more, those neurons then developed into an interconnected, functional brain network without forming tumors, something other stem cell paradigms seem to be at higher risk for that can contaminate the results of drug-testing in those models.
“We call them induced neural stem cells,” says Huang. “We can now use these cells in vaccination and in culture to screen for different Alzheimer’s modifying drugs.”
Goldstein has also successfully created “Alzheimer’s in a dish,” or a human stem cell model that may be beneficial for developing and testing different therapies. In the January 25 issue of Nature, he showed that he could take skin cells from people with sporadic and heriditary Alzheimer’s disease and reprogram them into working neurons.
“This kind of model, we think, will let us look at changes that happen early in people’s lives before they are diagnosed with Alzheimer’s disease at the doctor’s office,” says Goldstein. “The utility of this kind of approach is that it also allows us to start making different types of cells and look at their interactions. For example, astrocytes may be important to some of the changes we see in neurons, too. We can look at all the different types of cells and look at how they are behaving and how they respond to different drugs. It really extends our capabilities.”
Making it personal
One of the biggest advantages to these new stem cell technologies, Huang argues, is that they may allow us to personalize treatment for each person. Cholinesterase inhibitors don’t work for all people who have Alzheimer’s; these new techniques could allow researchers to take cells from individual patients and figure out which drugs will work for them. As Brinton argued, there are multiple pathways to developing Alzheimer’s disease and we should be seeking therapies for all of them.
Huang agrees. “This gets us closer to doing actual personalized medicine,” he says. “There are many patients with Alzheimer’s disease, but it may be that each patient has a unique feature for their cells, something that sets them apart from the rest. So we can then program cells from Patient A, Patient B and Patient C and see how each responds to different drugs. It will help us make sure that we are giving patients safe, effective drugs in the future.”
Brinton says the field is at a “watershed moment,” and is getting closer to conquering Alzheimer’s disease. “There’s great potential in these [stem cell models]. It’s obviously unproven at this point,” she says. “But I think it’s going to be very, very important to remain true to each patient and use different strategies to create specific and personalized therapies. There is not going to be one-size-fits-all drug for this disease. That’s simply not consistent with the data. And these models may help us understand the many phases, phenotypes, and trajectories involved in Alzheimer’s disease and help us tailor our therapeutic interventions accordingly.”