December 3, 2021 | LIFE | By Gabriella Casagrande | Illustration by Sierra Romero

Alexander disease is a rare neurological disease, with only about 500 cases since 1949. Originally, the disease was classified as a leukodystrophy, or a disease characterized by abnormality or destruction of the white matter in the brain.

A new study shows hope for this devastating diagnosis. But first, what happens in Alexander disease?

White matter is colored by myelin sheaths, which are fatty substances that form around areas of and protect our nerve cells while allowing efficient inter-cellular communication via electrical signals. More recently, it has also been considered an astrogliopathy, a disease of astrocytes, or cells in our central nervous system that support transmission of electrical signals.

The classification as an astrogliopathy is due to the presence of Rosenthal fibers in all cases. Rosenthal fibers are abnormal protein deposits in astrocyte cells. Their formation is caused by a mutation in the GFAP gene, a gene that encodes for filaments involved in cellular strength.

When mutated, the GFAP gene encodes for a shape-altered protein GFAP. These altered GFAP proteins then accumulate because the shape change doesn’t allow their formation together into filaments, creating Rosenthal fibers. The exact correlation between Rosenthal fiber formation and white matter destruction is unclear. This question is reinforced by the fact that Rosenthal fibers are found in all cases whereas leukodystrophy is not found in later-onset cases.

The symptoms of Alexander disease vary depending on the type, of which there are three: infantile, juvenile, and adult. Infantile Alexander disease is the most common and has a mortality of about six years old after symptoms appear by the age of two.

Symptoms of the infantile form include mental and physical delays, abnormal head size, and seizures. In most cases of Alexander disease, symptoms are progressive — more so in earlier-onset cases — and almost always fatal. 

Research on the disease is ongoing as it is progressive, fatal, and with no cure of standard treatment. A new study from researchers at University of Madison-Wisconsin has shown a potential treatment through a rat model. By first developing a rat model, the researchers were able to represent the white matter destruction and symptoms of human cases as well as track improvement, all of which were harder to track with earlier mouse models.

The developed treatment consists of antisense oligonucleotides, small pieces of DNA synthetically produced. These synthetic DNA pieces could target the genetic material that codes for GFAP proteins and tag them for destruction in the rat model. The result of a single treatment of the GFAP-targeted antisense oligonucleotides was long-lasting suppression of GFAP accumulation (i.e. Rosenthal formation).

When rats were treated before becoming majorly symptomatic, Alexander disease was virtually indetectable. In another set of rats, the disease was allowed to progress before treatment, which improved symptoms and, to some extent, reversed the white matter damage.

This study has large implications, as both a potential first treatment for a previously untreatable disease and providing more opportunity to learn the link between GFAP mutations and white matter destruction. The success with the rat model suggests future studies with mammals genetically close to humans, which may eventually improve the quality of life for Alexander disease patients by preventing or reversing symptoms.

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