CRISPR-Created Model of Fabry Disease Sparks New Insights

Kidney organoids designed with the same mutation as that present in Fabry disease can help investigators better understand how the disease functions, authors suggested.

A new report makes the case that stem-cell-derived kidney organoids can provide a meaningful model for understanding how Fabry disease affects the body and for developing therapies against the disease.

The study also shows some of the ways in which the CRISPR-Cas9 gene-editing platform can be used to advance research into various medical conditions, including rare diseases.

Fabry disease is a genetic disorder in which a deficiency or absence of lysosomal enzyme α-galactosidase A (α-Gal A) leads to defects in the glycosphingolipid pathway. This results in the buildup of globotriaosylceramide (Gb3) and related neutral glycosphingolipids within lysosomes, which can eventually lead to organ damage and multisystemic disease, including stroke, heart failure, and end-stage renal disease (ESRD), explained corresponding author Yong Kyun Kim, MD, of the Catholic University of Korea.

Renal involvement is common in males with Fabry disease and is also present in a nonclassical form of female Fabry disease, the authors said. Fabry nephropathy typically begins with microalbuminuria or proteinuria and eventually progresses to ESRD, which can be fatal in untreated patients with Fabry disease.

In recent years, enzyme replacement therapy (ERT) has been utilized in clinics. The therapy leverages agalsidase-α and agalsidase-β to clear up cellular deposits of Gb3 and lessen disease burden. Yet, the impact of the therapy is diminished when it is not initiated until the latter stages of the disease.

“ERT is also potentially limited by reaccumulation of Gb3 in podocytes after dose adjustment during the follow-up period and formation of neutralizing antidrug antibodies after infusion, which reduce the efficacy of ERT by increasing cellular Gb3 deposition and results in harmful clinical outcomes that include progressive loss of renal function,” the investigators wrote. “Thus, adjunct therapy to prevent the progression of renal disease toward ESRD is needed.”

In their new paper in Environmental & Molecular Medicine, Kim and colleagues explained how they explored Fabry disease using gene editing and kidney organoids. Organoids are synthetic, multi-cell tissues that can mimic an organ.

Kim and colleagues used human inducible pluripotent stem cells to create kidney organoids and then used the CRISPR-Cas9 platform in order to match the galactosidase alpha (GLA) gene mutation present in Fabry disease.

An examination of the organoids revealed they contained deformed epithelial tubular cells and podocytes, the authors explained, including dense lipid-like deposits in their cytoplasms.

“The organoids exhibited high oxidative stress levels, and decreased metabolism of the natural antioxidant glutathione,” they wrote.

The investigators then tried boosting glutathione, which is produced in the liver, and found that it led to an improvement in the organoids’ cellular structure and decreased oxidative stress.

“This study demonstrated that ERT not only ameliorated structural deformities but also reduced oxidative stress and increased the gene expression of kidney cells in Fabry kidney organoids, which means that Fabry kidney organoids are useful tools for investigating the efficacy of ERT and will contribute to the development of new forms of ERT,” the authors concluded.

Kim and colleagues added that the analysis they performed could easily be used to evaluate how Fabry disease affects other organs.

“The described methodologies are broadly applicable and adaptable to Fabry disease involving diverse tissues, including the heart, brain, and skin, and can be used immediately to experimentally investigate molecular pathways and novel treatments,” they wrote.


Kim JW, Kim HW, Nam SA, et al. Human kidney organoids reveal the role of glutathione in Fabry disease. Exp Mol Med. Published online October 15, 2021. doi:10.1038/s12276-021-00683-y