Seeking Therapies
Researchers are using cell-based high-throughput screening (HTS) assays to discover potential treatments for Krabbe disease. One proposed HTS assay is performed in cell-lines with the human GALC mutated protein with a specific flurogenic substrate also used to measure the GALC activity in dried blood spots in newborn screens for Krabbe disease, said Dr. Maegawa.
Another developed throughput assay is cell-based but uses neurologically relevant brain cells and measures accumulated psychosine, a cytotoxic natural substrate in Krabbe disease. The cell-line was established from the brain of naturally occuring mouse models for Krabbe disease called the Twitcher mouse.
This is an essential component of the myelin, but at nonphysiological high levels, psychosine becomes extremely toxic to myelin-forming cells, such as oligodendrocytes and Schwann cells.
“We are also looking at the manipulation of the biosynthetic psychosine, which is the extremely cytotoxic metabolite in Krabbe disease. If we find a molecule that normalizes the levels of psychosine, we will eventually be able to find a drug that will prevent the cytotoxicity of high levels found in Krabbe disease and to eventually arrest and prevent the demyelination that occurs in this disease,” said Dr. Maegawa.
“Gene therapy and cell therapy trials have shown progress in the Twitcher models by carrying a homozygous nonsense mutation in the GALC murine gene. Hopefully, a combination of these approaches will soon be used in clinical trials.”
—Erica Tricarico
Suggested Reading
Escolar ML, Poe MD, Provenzale JM, et al. Transplantation of umbilical-cord blood in babies with infantile Krabbe’s disease. N Eng J Med. 2005;352(20):2069-2081.
Jang DS, Ye W, Guimei T, et al. Cell-based high-throughput screening identifies galactocerebrosidase enhancers as potential small-molecule therapies for Krabbe disease. J Neurosci Res. 2016;94(11):1231-1245.
Ribbens J, Whiteley G, Furuya F, et al. A high-throughput screening assay using Krabbe disease patient cells. Anal Biochem. 2013;434(1):15-25.
Ribbens JJ, Moser AB, Hubbard WC, et al. Characterization and application of a disease-cell model for neurodegenerative lysosomal disease. Mol Genet Metab. 2014;111(2):172-183.
Wasserstein M, Andriola M, Arnold G, et al. Clinical outcomes of children with abnormal newborn screening results for Krabbe disease in New York State. Genet Med. 2016;18(12):1235-1243.