Borrowing from the cancer playbook to find treatment for Alzheimer's disease
In search of fresh ideas, researchers have begun to borrow a phrase or two from the more familiar language of cancer treatment.
Some scientists are studying precision medicine, or personalized medicine, which is routinely used to treat breast and colon cancers. Other researchers are focusing on immunotherapy, an effective form of medicine for skin, lung, kidney, bladder and other cancers.
This translation of the cancer-fighting vocabulary to Alzheimer's disease, though, is not always simple.
Adapting precision medicine
"In precision medicine, in order to apply the most effective treatment possible, doctors select treatments based on the patient's genetic profile," explained Dr. Christiane Reitz, assistant professor of neurology and epidemiology at the Columbia University Department of Neurology.
The first step when applying precision medicine to Alzheimer's disease is to learn "as many of the genetic variants as possible" that cause this common form of dementia, said Reitz, whose research focuses on identifying both genetic and non-genetic factors that contribute to changes in the brain.
"There are diseases that are caused by only one gene or very few genes," she said. Huntington's disease, a classic example, is caused by a single gene mutation: If you have the mutation, you will develop the disease.
Late-onset Alzheimer's, though, is nothing like Huntington's or even most diseases.
"There are likely more than a hundred genes involved in Alzheimer's," Reitz said. "We know some of them but not all. We need to identify the remaining ones."
In a recently published study, Reitz noted that scientists have mapped "27 susceptibility loci" for Alzheimer's disease: regions on the chromosome that are most likely to mutate and thereby contribute to the risk of that disease.
Since there may also be a variety of causes of Alzheimer's, scientists hope that they will be able to identify the specific cause of a patient's disease by sequencing his or her genetic profile, Reitz explained. "Then, the most effective treatment for that patient can be determined and applied."
Such is the case with one experimental drug presented last week at the 2018 Alzheimer's Association International Conference in Chicago.
Restoring 'cellular balance'
Dr. Harald Hampel, a professor at Sorbonne University in Paris, explained that the experimental drug, Anavex 2-73, a precision medicine candidate from specialty pharmaceutical company Anavex Life Sciences Corp., activates the Sigma-1 receptor.
A worthy target for precision medicine, the Sigma-1 receptor "is involved in several important pathways related to Alzheimer's disease," Hampel said. It reduces beta amyloid (the signature plaque deposits seen in the brains of deceased Alzheimer's patients) and hyperphosphorylated tau (the signature protein tangles also seen in patients' brains), he said. It also lessens oxidative stress and inflammation in the brain, both of which have been linked to aging and age-related diseases.
The advantage of targeting the Sigma-1 receptor is that it "activates the body's own defense mechanism to restore cellular balance," Hampel said.
In their study presented at the Alzheimer's conference, Hampel and his colleagues researched the drug's effect in 32 mild-to-moderate Alzheimer's disease patients. The study showed that "patients improved both cognition and activities of daily living" after taking the drug for 57 weeks.
"Some also experienced positive effects on insomnia, a common problem among Alzheimer patients, and improved sleep," Hampel said.
Beneficial effects, however, varied among patients based on their individual genetic profiles.
"We were able to identify certain genetic variations for certain patients that explain their improved response," Hampel said. Specific genetic features, shared by about 80% of the study participants, correlated with a strong, "clinically meaningful" response to the medicine, he said.
" 'Clinically meaningful' means that the improvements are noticeable for the patient and the people around the patient," Hampel said. Participants with the conducive genetic profile also showed improved scores on gold-standard tests of cognition and activities of daily living, the study presentation indicated.
Though only 32 Alzheimer's patients participated in the study, Hampel feels confident of the results.
"Genetic patient data is more precise, and therefore not many patients are required. Examples are genetic studies in oncology, where even smaller studies are performed," he said. The next step, which has already begun, is a larger safety study of the drug in 450 participants with Alzheimer's.
Ultimately, Hampel said, he and his co-authors follow the concept of precision medicine, which means "to treat the right patient with the right drug at the right time."
"Alzheimer's disease is a complex disease," he said. "The newest weapon in the fight against Alzheimer's disease might be your own body."
Lundbeck, a global pharmaceutical company focused on psychiatric and neurological disorders, also subscribes to this philosophy as it works to develop an immunotherapy for Alzheimer's patients.
Unleashing the body's natural response
It might be natural to think of the body's immune system as a guard dog, eager to attack any incoming pathogens. However, the immune system is less a dog and more a dance, an interaction of blood cells, chemicals and proteins -- a collaboration that is highly intelligent and carefully calibrated at once. Among the various proteins within the system are those known as "checkpoint proteins."
"There's a PD 1 checkpoint protein on an immune cell and a similar checkpoint protein, called PDL 1, on a normal cell," explained Dr. Doug Williamson, chief medical officer and vice president of US medical for Lundbeck. "This 'handshake' tells the immune system not to attack."
When it comes to cancer, these checkpoint proteins fail to do their job due to the fact that some tumors also produce PDL 1. By this simple act of identity theft, tumor cells can masquerade as normal cells and thwart the immune system.
Immune checkpoint inhibitors, then, are one type of cancer drug that is often made of antibodies able to trigger an immune response and which can turn off the ability of cancer cells to masquerade as normal.
Williamson and his colleagues at Lundbeck are developing a potential immune checkpoint inhibitor for Alzheimer's disease.
The theory behind the experimental immunotherapy drug is, why isn't the body attacking the toxic proteins, "recognizing them as foreign and toxic and eliminating them the way that it usually does?" Williamson said.
This immunotherapy, an antibody, could make the toxic proteins visible to the immune system, which could then destroy them and prevent them from causing cell death in the brain.
Though the drug has not been tested in humans, animal study data suggest that when antibodies bind to checkpoint inhibitors, they appear to reduce deposits of plaque in the brain, Williamson said. He added that "there's a lot of development work to go" before a safe and effective drug can be developed.
"I can't give you a specific timetable, but we're looking at six to 10 years before this treatment might become available," he said.
Clearing an FDA hurdle
Overall, he said, there is some good news yet also "a host" of challenges to develop effective and safe drugs for the treatment of Alzheimer's disease.
First among the difficulties is getting a drug across the blood-brain barrier, the membrane that surrounds the intellectual organ with the purpose of stopping that from happening, he said. Another challenge is monitoring what's happening inside the brain.
"Increasingly, there are imaging technologies that allow you to look at deposited amyloid plaque and even deposited tau in the brain," Williamson said. These deposits of amyloid plaque and tau tangles are considered "biomarkers" of Alzheimer's disease.
A past study as well as the new results for an experimental drug jointly produced by Eisai Co. Ltd. and Biogen Inc. have shown that certain treatments can reduce the buildup of plaque in the brain. But what has not been demonstrated to the satisfaction of the US Food and Drug Administration is an association between a reduction in the plaque biomarker (as seen on a scan) and positive changes in the mental functioning of patients, Williamson said.
The good news is that once a link has been established between changes in biomarkers and a beneficial change in a patient's cognitive abilities, the FDA has indicated it will no longer require drug developers to prove that each potential new drug can modify Alzheimer's disease, Williamson said.
Once a firm connection is established, drug developers will need only to show their candidate drugs affect the biomarkers.
"An analogy to this would be cholesterol-lowering drugs and heart disease," Williamson said. Once the link between lowering cholesterol and heart disease was established, scientists no longer needed to conduct thousands of patient studies to show that a drug reduced heart disease. "You just needed to show you could reduce cholesterol."
One final challenge when developing Alzheimer's drugs is recruiting patients.
Since none of the available treatments can slow or stop the progress of Alzheimer's, a lot of people don't really want to know whether they're going to develop it, Williamson said. Meanwhile, past studies have failed because the participants were in the later stages of the disease.
"If you wait until people have got significant cognitive problems, then the damage is already done," Williamson said. "I personally think it's going to get better once we have an effective treatment."
Car manufacturers seek tech solutions to hot car deaths
Safety advocates have just scored a win as automaker Nissan announced plans Tuesday to make rear door alerts standard in eight vehicle types by model year 2019.
The system will notify drivers if the rear door was opened before a trip but not reopened after the car is parked and the ignition is turned off, with an initial display in the instrument panel and a series of discrete honks. Nissan aims to have the rear door alerts in all four-door trucks, sedans and SUVs by model year 2022, the company said in a statement.
"We kept reading all these incidences of children accidentally left in cars and we were really worried," said Marlene Mendoza, a mechanical engineer at Nissan who developed the technology with fellow engineer and mother, Elsa Foley.
They asked themselves, "Is there something we can do?" Mendoza said.
They started brainstorming and working on the concept in 2014 but the idea for the alert came while Mendoza was pregnant and accidentally left a pan of lasagna in her backseat overnight. She said the car smelled for days after but it made her wonder about what could happen if she left something -- or someone -- more important back there.
"It can help so many people at different levels," she said.
GMC also developed a rear seat reminder feature in most of their 2018 models to help remind parents to look before they lock. Hyundai created a reminder system that detects children's movements in the backseat.
While child safety advocates are pleased car companies are implementing technology, they say it cannot stop there.
"I think all alert systems can be helpful," said Miles Harrison, of Purcellville, Virginia. "But alert systems alone will not work. It needs to be an alert system and a regular messaging system somehow. Because most people, myself included, can't believe this can happen to them. It's so unbelievable. You can't walk in someone else's shoes."
Harrison is one of the hundreds of parents and caregivers who have lost a child to vehicular heatstroke. His one-and-a-half-year-old son Chase died in July 2008 after Harrison accidentally left him in the backseat of his car and went to work instead of dropping him off at daycare. Harrison said it's imperative that more warnings and messaging about the dangers of leaving a child behind get shared in birthing centers, daycares and schools.
"It is terribly hard," he said. "I think part of it is this intense guilt that I still feel. The other part is I don't want parents to have to go through what I put my family through. I don't want them to have to wake up every morning like I do."
The National Highway Traffic Safety Administration created the Heatstroke Awareness Challenge in July to encourage the public to create and share short videos that spread awareness about heatstroke. The organization encourages parents and caregivers to check the backseat before locking, keep the keys out of reach of children to prevent them from getting in alone, and to take action if a child is left alone in a vehicle.
"As temperatures around the country continue to rise, and summer schedules change routines, we recognize, tragically, that the heatstroke death toll is only going to climb," said Heidi King, the Deputy Administrator of the National Highway Traffic Safety Administration in an op-ed. "It's up to everyone -- parents, guardians, and even bystanders -- to end these senseless and preventable tragedies."
A car's temperature can shoot up by 20 degrees in just 10 minutes and because of climate change, more days are expected to be hotter, according to the American Academy of Pediatrics. A child's body overheats faster than an adult's and starts shutting down at 104 degrees Fahrenheit. Twenty-six children have died so far from heatstroke in 2018 alone, according to the US Department of Transportation.
"We've introduced the Hot Cars Act and it would require a reminder alert system in all new vehicles to prevent hot car deaths," said Amber Rollins, director of the safety organization KidsAndCars.org. "It's not a prescriptive bill, so it doesn't call for any specific type of technology but it calls for the National Highway Traffic Safety Administration to take a look at what's available and decide what the best solution would be."
The bill was attached to the federal Self Drive Act, which was introduced and passed in the House in 2017. Its companion in the Senate, the AV Start Act, passed through the Commerce, Science and Transportation Committee but awaits confirmation by the full Senate. If the bill doesn't make it through, Rollins said it will be reintroduced in the next congressional session.
Safety can be looked at from several angles, Rollins said, citing examples of technology installed in the vehicle or added to car seats.
The child seat and stroller company Evenflo created SensorSafe, a chest clip that connects with a wireless receiver to trigger an alert. When the driver reaches their destination and turns off their vehicle, it sounds an audio reminder that there's a baby in the back.
Evenflo's parent company also makes car seats that use an app for an additional prompt.
There are even more sophisticated systems that would sense a child's presence through movement or carbon dioxide sensors, she added.
"You can also start doing something today, like putting your bag in the back," said Emma Klingman, a board member of the Sofia Foundation for Children's Safety. "It doesn't cost any money; you don't need to buy anything; you don't need a new car. We're really hoping we can help prevent this from happening to people even in the meantime as technology is being developed."