NYSCF Method Advances Understanding of Alexander Disease

A team from the Beckman Research Institute of City of Hope led by Dr. Yanhong Shi reports in Cell Stem Cell that it has developed a new stem cell model to assess possible treatments for a rare nervous system disorder called Alexander disease. The study employs a protocol developed by NYSCF scientists for generating oligodendrocytes and astrocytes, two fundamental types of support cells in the brain. NYSCF Senior Principal Investigator Valentina Fossati, PhD, who led the development of the protocol, is a co-author.

Alexander disease is caused by a genetic mutation that adversely affects astrocytes. Patient brains also display a depletion of myelin (the fatty substance that surrounds nerve fibers and helps them send signals). As a result of the myelin depletion, patients with Alexander disease often show symptoms such as movement difficulties, intellectual disability, and delayed development. Yet it is still an open question how malfunctioning astrocytes lead to reduced myelin – since research in animal models of the disease could not answer this question, this team turned to stem cells.

Using NYSCF’s protocol, the team generated astrocytes from induced pluripotent stem cells derived from patients with Alexander disease. They compared the diseased astrocytes to those generated from healthy controls to explore differences in how the cells behaved. They found that the mutated astrocytes secreted a certain protein that sparked inflammation and suppressed the development of myelinating cells, leading to the onset of Alexander disease.

Using CRISPR gene editing, the researchers corrected the disease mutation and observed that the astrocytes behaved more like healthy astrocytes, reversing many of the disease features described above. This confirmed that the differences were caused by the disease mutation, and that this stem cell model could recapitulate key disease features to help researchers understand the relationship between faulty astrocytes and depleted myelin. This new stem cell model of Alexander disease also provides a way for researchers to test therapeutic interventions in future studies.

This work will help advance our understanding of Alexander disease as well as other neurodegenerative diseases (such as Alzheimer’s disease, Parkinson’s disease, and ALS) that are suspected to involve astrocytes. It is challenging to derive astrocytes and oligodendrocytes from stem cells, so NYSCF’s protocol stands to benefit researchers who are developing stem cell models for many of these different diseases.