Bridget Perkins turned on the slicing machine and got to work.
On a lab bench at the Stark Neuroscience Institute at the Indiana University School of Medicine, a sharp blade cleanly sliced through a small section of a mouse’s brain, providing a delicate shave smaller than a fingernail and thinner than paper.
Perkins, a research analyst, moved the blade over and over to produce more shavings. “You get these very thin slices in different parts of the brain,” she said.
The machine, called a sliding microtome, can slice a single mouse brain into more than 500 shavings. A lab worker stains it with an antibody and places it on a slide for study.
All of these brain slices are intended to help scientists solve one of the most difficult mysteries of modern medicine: how to identify the factors that put people at the highest risk of Alzheimer’s disease, and to help develop treatments. .
That’s a big challenge. Alzheimer’s disease kills more than 100,000 Americans a year and is her fifth leading cause of death among Americans over the age of 65. There is no cure for this disease. Current medications only provide temporary relief of symptoms and do not slow the decline.
Last month, the IU School of Medicine announced a $48.8 million five-year grant from the National Institute on Aging, a division of the National Institutes of Health.・Onset of Alzheimer’s disease.
The goal is to discover new insights into diseases that have puzzled researchers for decades.
The program, which the NIH helped establish in the medical school in 2016 and had totaled $35.7 million in funding before its most recent grant, has developed 40 new gene mutation models.
As with most scientific research, this process is time consuming and expensive. The researchers say they have identified several promising targets in the brain and compounds that have been demonstrated to reach targets that may slow disease progression.
Bruce Lamb, Executive Director of the Stark Institute for Neuroscience and Professor of Alzheimer’s Disease Research at the School of Medicine, said:
But he believes it will be several before researchers can advance these compounds from mice to humans in large-scale clinical trials, either alone or with partners in the biotech or pharmaceutical industries. I admit that it will likely take years.
Decades of Discouragement
The history of research into treatments for Alzheimer’s disease is fraught with setbacks. Between 1998 and 2017, 146 drug candidates failed clinical trials, according to the Biopharmaceutical Corporation of America, a coalition of the world’s largest pharmaceutical companies that includes Indianapolis-based Eli Lilly.
At the same time, only four have received U.S. Food and Drug Administration approval, and these drugs treat symptoms only. The progression of the disease cannot be slowed.
According to the Alzheimer’s Association, development costs for a typical Alzheimer’s drug are $5.6 billion, a process that takes 13 years from preclinical testing to regulatory approval. For comparison, the estimated cost of developing cancer treatments is $793.6 million per drug.
“Despite significant progress in Alzheimer’s disease research and drug testing in recent years, the field still faces the challenge of translating basic scientific discoveries into effective treatments and care practices,” said the Alzheimer’s Association. Rebecca Edelmeyer, senior director of scientific engagement at , told IBJ.
“At the same time, genetically engineered rodent models of juvenile-onset Alzheimer’s disease will provide insight into the genes involved in Alzheimer’s disease in humans and how they lead to the devastating brain changes observed in Alzheimer’s disease. “It has provided important insights,” she added. It helps promote the development of law.”
In fact, more potential treatments are underway. Last month, Japanese pharmaceutical company Eisai and its US partner Biogen announced a study of an Alzheimer’s drug that slowed cognitive decline by 27% in clinical trials. Year.
Meanwhile, Lilly is testing an Alzheimer’s drug called donanemab in a clinical trial. The effort follows the recent disappointing results of his three high-profile Alzheimer’s drugs, which the company has spent more than $3 billion developing.
According to the British medical journal The Lancet, scientists have offered a number of explanations for the failure of Alzheimer’s trials, among them wrong dosages, wrong treatment targets and patients with too advanced disease. It includes the fact that the test has started.
But perhaps at the top of the list is our poor understanding of the biology of Alzheimer’s disease.
attack on the puzzle
So laboratories like this are doing their part to help us better understand the basic science of disease.
On the IU lab bench, Chris Lloyd flicked through a series of magnified slides of brain slices on the computer.
The slides are lit up with brightly colored images. Green indicates abnormal and decaying neurons. Blue shows clumps of protein called beta-amyloid plaques that are often associated with Alzheimer’s disease. Red shows white blood cells in the brain, which normally cluster around plaque to fight invading proteins.
“We use fluorescence microscopy to illuminate different wavelengths of light that excite specific regions,” says Lloyd, immunohistochemistry project manager. colorful image.
Laboratories have studied thousands of mice to create research models to identify genetic and environmental risk factors for disease.
The program includes partners from The Jackson Laboratory in Bar Harbor, Maine (providing mice). University of Pittsburgh School of Medicine. Sage Bionetworks is a Seattle non-profit organization that promotes open science.
The official name of the consortium is Model Organism Development and Evaluation for Late-Onset Alzheimer’s Disease, or MODEL-AD for short.
The lab has more than 1,000 mice on hand for research, Lam said. He declined to let IBJ see or photograph live mice, but he told his IBJ that one of his members of the research team, Perkins, sliced mouse brains. and allowed to see it used for analysis.
Mice are preferred by Alzheimer’s researchers because their anatomy, physiology, and genetic make-up resemble those of humans.
from scratch
A neuroscientist with a PhD in molecular biology, Lam came to Indianapolis from the Cleveland Clinic to launch this program. There he studied the underlying disease mechanisms of Alzheimer’s disease. This includes genetic factors involved in the metabolism and accumulation of proteins that make up Alzheimer’s disease. Increase disease-related plaque deposits.
His first job was to set up a new laboratory in a space on West 15th Street just south of the Methodist Hospital. This space had not yet been built and was just a dirt floor.
“We literally started with nothing,” Lam said. “His first year was just hiring staff, setting up the lab, getting the animals ready, and starting the process of sequencing DNA that could be used as markers in disease research.”
His researchers started with all the information from human genetics studies that identified risk genes for late-onset disease, generally defined as onset beginning after age 60 or 65.
They had a lot of help. Worldwide, a large group of researchers has identified genetic risk genes and mutations associated with high or low disease risk.
“We took all that information and translated it into a mouse,” says Lamb. “Can we model these particular genes in mice? Some of them are possible because the genes are conserved —[or sequenced]—and can have essentially the same mutations. Then we have to come up with new ways to model them. ”
Over the past six years, researchers have combined different genetic risk factors to see if a particular combination of genetic risks causes disease.
Using a process called genome editing, researchers can make precise genetic modifications to mice to discover high or low risk of Alzheimer’s disease.
Researchers can combine genetic variants in a variety of ways. One protein, called apolipoprotein E (APOE for short), is involved in fat metabolism and has been linked to Alzheimer’s disease. A genetic mutation called APOE 4 quadruples his lifetime risk of developing Alzheimer’s disease, Lamb said.
types and subtypes
The researchers are also testing the hypothesis that a so-called Western diet, high in fat and sugar, may increase people’s risk of Alzheimer’s disease. It is complex, meaning there is likely to be no one-size-fits-all treatment for patients.
“There are some genetic variants that really seem to respond to the effects of diet, and some that don’t really match at all,” Lamb said.
The widely held theory that there are many types and subtypes of Alzheimer’s disease makes this task more difficult. So researchers are busy identifying all the targets in the brain that different people with the disease might respond to.
Adrian Oblak, Principal Investigator of the MODEL-AD Consortium, PhD in Anatomy and Neurobiology, said:
The consortium is just one of many research projects at the IU School of Medicine focused on Alzheimer’s disease. The Indiana Center for Alzheimer’s Disease Researchers was founded in 1991 to connect medical school researchers and resources with thousands of researchers.
Meanwhile, three years ago, the school established a drug discovery center with a $36 million federal grant to accelerate the development of promising Alzheimer’s drugs.
So far, mice have helped researchers better understand the brain and disease. But the process of turning science into therapy promises to be a long road ahead. Already Lam and his colleagues have come a long way, with support from partners in the biotech and pharmaceutical industries.
“We have had initial discussions with several different companies that may be interested,” Lam said. “That’s what we’re working on.” •
