From molecule to medicine: pursuing insight and new treatment for Alzheimer's disease

For a new drug to become a medicine, the process is long and expensive. The journey can take more than a decade, with recent drug development cost estimates as high as $2.6 billion per drug, and this is without a guaranteed Food and Drug Administration (FDA) stamp of approval.

For dementia and Alzheimer's disease (AD), treatment options are limited, and the chances of an AD drug making it from molecule to medicine are among the worst in any therapeutic area. This is discouraging for patients and families, and can instill hesitation in companies looking to invest in AD drug development.

With an urgent need for better treatment, researchers are finding new insights. A recent pipeline analysis shows that 35 different drugs are optimistically close to FDA-approval to treat AD. However, well before that final hurdle is cleared, laborious research is conducted in cell cultures, animal models, and humans. ScienceLife spoke with some people at UChicago conducting the research that contributes to AD insight and patient care.

At the bench

One major objective in AD research is to find ways to clear or prevent the development of amyloid plaques. These plaques gradually develop in the brain and are thought to cause the cellular disruption that drives the pathology of the disease. A greater concentration of amyloid is thought to coincide with more symptoms and overall greater disease progression.

In the lab of Sam Sisodia, PhD, he and his team are developing lab models to discover the cellular and genetic forces that underlie amyloid. "We genetically program mouse models to exhibit certain AD characteristics in the brain, and then we interfere with that process," he says.

Sisodia's lab also looks at how genes play a role in neurogenesis, or the forming of new, healthy cells. Neurogenesis may be a protector against the progression of AD. Their group also looks at how environmental conditions and the microbiome, or bacteria in the gut, can affect brain function to alter neurogenesis.

To help tackle these massive questions, postdoctoral fellow Myles Minter, PhD, starts from the top level. "To see if the microbiome can alter characteristics of AD, we change the microbiome and then measure amyloid. One way to perturb the microbiome is to administer antibiotics he says. Referring to their finding last year in Scientific Reports, "what we found was a reduction of amyloid in mice that received chronic antibiotic treatment." These latter studies were performed in collaboration with Eugene Chang and Vanessa Leone in the Department of Medicine.

In more recent studies performed with Chang and Leone and investigators in the Microbiome Center, they were interested in determining the critical timepoint the antibiotics needed to be given and how long the effects would last. In these experiments, "we gave mice just one week of antibiotics, and six months later we saw the same results," says Sisodia, referring to how the brief antibiotic regimen reduced amyloid and altered the microbiome profile six months later.

While the findings are exciting, "we aren't saying that antibiotics can be a cure, or even a treatment, but we can certainly use this model to alter the microbiome and look at its effects on amyloid, which leads to future studies," says Minter.

Controlled experiments like these are crucial for developing lab models that produce valid data. After sufficient preclinical data are gathered, a drug moves to the clinical trial phase where it is tested in humans. One of the 35 drugs currently in the AD pipeline is called aducanumab, which selectively targets certain forms of amyloid. A breakthrough finding published in Nature last year suggests the drug can greatly reduce amyloid buildup, and slows AD progression.

Similar to preclinical studies, clinical trials take time, money, and patience. If aducanumab makes it through and gains FDA-approval, its prescription won't be available until 2023.

In the Clinic

Meanwhile, UChicago neurologist James Mastrianni, MD, PhD, Director of the Center for Comprehensive Care and Research on Memory Disorders, who specializes in Prion diseases, deals firsthand with patients with neurodegenerative disorders. He is familiar with the challenges that accompany the clinical trial landscape as he runs clinical trials on Alzheimer's disease.

A recent AD drug that fell short in late stage clinical trials was bapineuzumab, which selectively targets amyloid. Although the results were disappointing, there was an interesting takeaway. "In a small subset of patients with the mild stage of the disease, the drug seemed to fair better," says Mastrianni.

If these drugs work better in people in the early stages of the disease, there lies a dilemma: these same people do not experience a lot of symptoms and are more likely to deny they need the help.

"Sometimes the problem is denial, but other times it is the disease itself that can rob people of their insight," says Dr. Mastrianni. Finding people to participate that fit the study criteria is difficult. "These dementias often coincide with concurrent diseases that can automatically exclude patients from participating. You need to be a perfect patient it is not easy."

Recently, a few patients have fit these specific criteria and participated in a clinical trial at UChicago where they received a beta secretase (BACE) inhibitor, a cutting edge anti-amyloid drug still in development which disrupts the metabolism of the precursor protein that makes amyloid.

To supplement these potential new treatments, more sensitive diagnostic tools are now available to help ensure the drugs are given to patients most suitable to receive them.

With these new tools, Sisodia remains optimistic in the wake of recent clinical trial failures. "From a mechanistic and experimental design standpoint, we know why the trials failed, and we know which targets to hit next it's a good place to be."