Genetic Engineering Publications - GEG Tech top picks

Fabry disease is caused by a genetic deficiency of α-galactosidase A (GLA), leading to the accumulation of its substrates such as globotriaosylceramide and globotriaosylsphingosine. Researchers have therefore developed a modified enzyme, modified α-N-acetylgalactosaminidase (mNAGA), to cure Fabry disease by changing the substrate specificity of NAGA to that of GLA. In this study, researchers tested whether genome-editing transplantation of mNAGA-secreting induced pluripotent stem cells (iPS) cells could deliver GLA activity in vivo. They therefore generated mNAGA-secreting iPS cells by TALEN-mediated knock-in at the AAVS1 site, a refuge locus. Furthermore, to exclude possible immunogenic reactions caused by endogenous GLA from iPS cells in patients, they disrupted the GLA gene by CRISPR-Cas9. When cardiomyocytes and fibroblasts from the Fabry model without GLA activity were co-cultured with mNAGA-secreting iPS cells, GLA activity was restored by mNAGA-expressing cells in vitro. Next, they transplanted the mNAGA-secreting iPS cells into the testes of mouse models of Fabry disease. After 7 or 8 weeks, GLA activity in the liver was significantly improved, although no recovery of activity was observed in the heart, kidneys or blood plasma.

Glaucoma is a neurodegenerative disease that causes vision loss and blindness due to a damaged optic nerve. Unfortunately, there is currently no cure. In a paper recently published in Communications Biology, researchers found that restoring mitochondrial homeostasis in diseased neurons can protect optic nerve cells from damage. The research team used induced pluripotent stem cells from glaucoma and non-glaucoma patients as well as clustered regularly spaced short palindromic repeats (CRISPRs) from human embryonic stem cells with glaucoma mutation. Using optic nerve stem cell differentiated retinal ganglion cells, electron microscopy and metabolic analysis, the researchers identified glaucomatous retinal ganglion cells with mitochondrial deficiency with a higher metabolic load on each mitochondrion, which leads to mitochondrial damage and degeneration. However, the process could be reversed by enhancing mitochondrial biogenesis with a pharmacological agent. The team showed that retinal ganglion cells are very efficient at degrading bad mitochondria, but at the same time produce more to maintain homeostasis.