a therapy eliminates brain plaques

With the goal of reducing the frequency of treatment and potentially improving the effectiveness of anti-amyloid therapy, researchers from the School of Medicine of the Washington University in St. Louis (United States) have designed a new cellular immunotherapy that requires a single injection to prevent the development of amyloid plaques when administered before they begin to form in mice.

According to it, a single treatment in mice that had already developed plaques reduced the number of amyloid plaques by half. The study is published in ‘Science’.

A therapy inspired by cancer treatments

The new generation of drugs for the disease Alzheimer’s (the first to have been shown to change the course of the disease) usually prolongs the independent life of patients by 10 months. Monoclonal antibodies reduce the buildup of amyloid, a harmful protein, in the brain and require high-dose infusions once or twice a month.

Like therapies with CAR-T cells Used for cancer treatment, in which T cells of the immune system are genetically modified to attack cancer cells, this new approach gives the cells (in this case, neurons called astrocytes) with a CAR localization mechanism so that they attach to a target and destroy it.

These new CAR-astrocyte cells have characteristics that transform them into supercleaners that remove harmful proteins from the brain that contribute to cognitive decline.

“This study marks the first successful attempt to engineer astrocytes to specifically target and eliminate amyloid beta plaques in the brains of mice with Alzheimer’s disease,” said the study’s lead author, Dr. Marco Colonnaprofessor of Pathology at WashU Medicine.

“Although more research is needed to optimize the approach and address potential side effects, these results open an exciting new opportunity to develop CAR astrocytes as immunotherapy for neurodegenerative diseases and even brain tumors.

The results that have surprised researchers

Alzheimer’s disease begins with a sticky protein called amyloid beta that builds up to form plaques in the brain, triggering a chain of events that results in brain atrophy and cognitive decline. Microglia, immune cells residing in the brain, are responsible for clearing brain waste, but can become dysfunctional when overloaded in the context of neurodegenerative disease.

To reduce the cleaning load on microglia, the team of researchers transformed astrocytes, the most abundant cell type in the brain, into amyloid cleaning machines. He custom designed and delivered a gene to astrocytes that encodes the chimeric antigen receptor (CAR) via a harmless virus injected into mice.

CAR, now present on the surface of astrocytes, allowed the cells to capture and engulf amyloid beta proteins. With their newly acquired ability, astrocytes, usually responsible for keeping the brain tidy, focused their efforts only on clearing amyloid beta plaques in mice prone to their accumulation.

Mice carrying genetic mutations that increase the risk of developing Alzheimer’s develop amyloid beta plaques that saturate the brain by six months of age. First, they injected the virus carrying the CAR gene into two groups of mice: young mice before developing plaques and older mice with brains saturated with plaques. Then they waited three months.

As the younger mice aged, CAR astrocytes prevented the development of amyloid beta plaques. At almost six months of age, when untreated mice normally have their brains saturated with harmful plaques, the brains of the treated mice were free of plaques. On the other hand, older mice with brains saturated with plaques at the time of treatment experienced a 50% reduction in the number of amyloid beta plaques compared to mice that received an injection of a virus lacking the CAR gene.

They seek to continue improving their CAR-astrocyte immunotherapy

The researchers have filed a patent, with the help of the WashU Office of Technology Managementrelated to the approach used to design CAR astrocytes.

“Consistent with antibody treatments, this new CAR astrocyte immunotherapy is most effective when administered in the early stages of the disease,” the researchers report. “But where it differs, and where it could make a difference in clinical care, is in the single injection that was able to reduce the amount of harmful brain proteins in mice.”

In future studies, the authors seek to further improve their CAR-astrocyte immunotherapy, refining its design so that it better targets harmful proteins, while ensuring the absence of detrimental effects on normal brain cell functions. Furthermore, by adjusting the CAR-homing device to recognize specific markers in brain tumors, they could modify the function of astrocytes, going from cleaning waste to directly destroying tumor cells. This approach could offer a promising new avenue for treating brain tumors and other diseases of the central nervous system.