After 30 years, scientists finally have a drug for a deadly brain disease

Alexander disease can interfere with movement, thinking, and automatic bodily functions such as breathing and heart rate. Zanvastro is the first and only approved disease-modifying treatment for the condition, meaning it targets an underlying biological process responsible for the disease rather than simply relieving its effects.

The drug emerged from more than three decades of scientific research at the University of Wisconsin-Madison's School of Veterinary Medicine and Waisman Center. Much of that work took place in the laboratory of Albee Messing, professor emeritus of comparative biosciences and former director of the Waisman Center, whose discoveries helped make the treatment possible. Ionis Pharmaceuticals collaborated in developing the drug.

Clinical trials offered encouraging results. Patients receiving Zanvastro generally experienced stabilization of their motor function, and some showed improvements in their ability to move.

"This is a wonderful and long-awaited day for the Alexander disease community," Messing says.

Alexander Disease: A Rare and Devastating Brain Disorder

Alexander disease affects fewer than one in every million people worldwide. Although exceptionally uncommon, its consequences can be severe, with symptoms that gradually interfere with everyday activities and essential bodily functions.

People with the disorder may develop seizures, lose previously acquired developmental abilities, experience increasing difficulty walking or moving, and struggle with speaking or swallowing. Some also develop dangerously elevated pressure inside the brain.

The disease does not follow a single predictable course. Symptoms may first emerge during infancy, childhood, or adulthood, and their severity and progression can differ depending on when the condition begins.

For decades, doctors could offer supportive care and treatments to ease individual symptoms, but they had no approved medication capable of targeting the disease itself.

An Unexpected Discovery Revealed the Genetic Cause

The breakthrough can be traced to research Messing conducted with Michael Brenner, professor emeritus of neurobiology at the University of Alabama at Birmingham. In the late 1990s, their work identified the genetic changes responsible for Alexander disease, providing scientists with a specific biological target for developing treatments.

The discovery began with an unexpected result in laboratory mice.

Messing and Brenner had genetically engineered mice to produce unusually high amounts of a protein known as glial fibrillary acidic protein (GFAP). This protein is normally found in astrocytes, specialized cells that help support and maintain healthy function in the brain and spinal cord.

To the researchers' surprise, the modified mice developed abnormal protein deposits throughout their brains. These deposits appeared inside astrocytes and closely resembled the distinctive abnormalities seen in people with Alexander disease.

"We had, really without intending to, created a mouse that produced these classic lesions of Alexander disease," Messing says.

The abnormal deposits, called Rosenthal fibers, are a defining characteristic of the disorder. Additional genetic studies involving people diagnosed with Alexander disease confirmed that mutations in the gene responsible for producing GFAP were the underlying cause.

"This provided an obvious and specific strategy for therapy -- the GFAP protein," Messing explains.

Identifying the genetic cause also made diagnosing the condition much simpler. Instead of relying on invasive brain biopsies to look for characteristic tissue abnormalities, doctors could use genetic testing from a blood sample to identify the mutations associated with the disease.

Scientists Develop a Drug That Targets Harmful Protein Buildup

Once researchers understood the role of GFAP, their next challenge was finding a way to reduce its production and prevent damaging levels of the protein from accumulating in brain cells.

Messing joined forces with Tracy Hagemann, an associate research professor at the Waisman Center, to create improved rodent models of Alexander disease. These models more closely reproduced important features of the disorder, giving scientists a way to investigate potential treatments before testing them in people.

The team focused on a straightforward idea: If excessive GFAP contributes to the disease, lowering the amount produced might help protect the nervous system.

In collaboration with Ionis Pharmaceuticals, the researchers pursued a technology known as antisense oligonucleotides (ASOs).

These treatments use short, specially designed pieces of genetic material to interfere with instructions that cells use to manufacture particular proteins. Rather than targeting every protein in a cell, an ASO can be designed to reduce production of a specific one.

For Alexander disease, that target was GFAP.

The experimental treatment produced promising results in rodents, supporting the decision to move forward with human testing. A clinical trial began in the summer of 2021.

Zanvastro uses this same targeted strategy. By limiting GFAP production, the drug aims to reduce the buildup of the protein before it can cause additional damage.

Because the treatment needs to reach the central nervous system, it is administered through an injection into the spinal canal. A trained healthcare professional gives the injection once every three months.

Clinical Trials Show Improvements in Walking and Movement

The human trial provided evidence that lowering GFAP could offer meaningful benefits to people living with Alexander disease.

Ionis Pharmaceuticals conducted the international study across 13 clinical sites, enrolling 54 patients to evaluate the treatment's safety and effectiveness.

After receiving Zanvastro for a little more than a year, treated patients demonstrated significantly better walking speeds than patients who had not received the drug.

The results also indicated that treatment could stabilize motor function, an important outcome for a progressive disorder that can steadily undermine a person's ability to move independently. Some participants experienced improvements in motor performance.

These findings helped establish Zanvastro as the first treatment approved to modify the underlying disease process in Alexander disease, rather than focusing exclusively on symptom relief.

The FDA approval covers people with Alexander disease across the full age spectrum, from infancy through adulthood.

Zanvastro is expected to become available in the United States in the weeks following the approval. Outside the United States, access to the drug will be handled through a licensing agreement between Ionis Pharmaceuticals and Recordati, a major pharmaceutical company headquartered in Italy.

A 30-Year Scientific Journey Offers New Hope

For Messing and his colleagues, the approval represents the culmination of more than 30 years of research, beginning with basic investigations into brain cell biology and eventually leading to a treatment for patients.

What started as an unexpected finding in genetically modified mice helped reveal the cause of an extremely rare disease, transformed how doctors diagnose it, and provided the foundation for developing a drug.

The achievement is also an example of translational research, the process of turning discoveries made in laboratories into treatments that can directly benefit patients.

Throughout that journey, individuals living with Alexander disease and their families played an essential role by supporting the research and participating in studies.

"The whole program of research would not have been possible without the support and participation from the patient and family community, to whom we will always be grateful," Messing says.