Potential treatment for Alexander disease

Alexander disease refers to a progressive disease of cerebral white matter, commonly detected in
infants and children. The neonatal form appears within the initial 30 days following birth, and is
characterized by gastrointestinal symptoms, neurologic symptoms, stiffness in legs and arms,
seizures, intellectual disabilities, developmental delay, and usually death within two years.
Despite no current treatment, Tracy Hagemann and collaborators conducted a new study at the
University of Wisconsin-Madison using a rat model of this disease to develop a prospective
treatment for the characteristically fatal disorder.
According to Hagemann, Alexander disease generally comprises the disintegration of the white
matter of the brain, frequently remains undiagnosed until the appearance of pronounced
symptoms. A characteristic feature of this disease is the development of Rosenthal fibers, which
are abnormal protein aggregates generated by a mutation in the GFAP gene that produces glial
fibrillary acidic proteins.
Hagemann and collaborators had developed a mouse model three years ago to demonstrate the
role of antisense oligonucleotides in eliminating Rosenthal fibers and lessening GFAP.
Nonetheless, mice exhibit few symptoms of Alexander disease, thus making it difficult to assess
significant impact of the treatment on the quality of life or behavior. Clinicians usually consider
Alexander disease as a type of leukodystrophy, manifested by white matter damage. This
pathological phenomenon was not observed in the mouse model. Therefore, rats were considered
a better choice for a preclinical model.
The researchers created a rat model that could reflect damage of the white matter and associated
physical symptoms manifested in patients. The model provided better opportunities to assess
symptom improvement in response to antisense oligonucleotide treatment. The model displayed
myelin damage, high aggregates of GFAP, extensive formation of Rosenthal fibers all over the
spinal cord and brain, high mortality, and motor injury. It was difficult to discriminate rats that
underwent antisense oligonucleotide treatment before the development of key physical
symptoms from their healthy complements. Following treatment initiation, severely affected rats
not only displayed extreme improvement in symptoms but also underwent a reversal of white
matter damage.

Hagemann mentioned that antisense oligonucleotides work by eliminating the Rosenthal fibers,
thus preventing the disease onset at an early stage. Moreover, this treatment can reverse the
disease phenotypes at a later stage. Findings of this study should be attributed to the far-reaching
research by Messing on Alexander disease, conducted over the previous two decades. Besides
paving the groundwork for human trials, the animal model flagged the approach to unravel
several facets of Alexander disease that are unclear, together with the novel prospect to explore
the association between white matter damage and GFAP mutations in mammals.
References
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Messing, A., Brenner, M., Feany, M. B., Nedergaard, M., & Goldman, J. E. (2012). Alexander
disease. Journal of Neuroscience, 32(15), 5017-5023.
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(2018). Antisense suppression of glial fibrillary acidic protein as a treatment for Alexander
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Hagemann, T. L., Powers, B., Lin, N. H., Mohamed, A. F., Dague, K. L., Hannah, S. C., ... &
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