Amelia Morrone

TL;DR: Researchers generated a human induced pluripotent stem cell line from a patient with GM3 synthase deficiency using a self-replicating RNA vector, characterizing the line's normal karyotype, pluripotency, and ability to differentiate into three germ layers.

Abstract: Novel pH-sensitive drug delivery systems offer significant potential for personalized medicine by enabling targeted therapy and minimizing side effects. These systems are designed to release therapeutic agents in acidic environments to achieve localized pharmacological effects. Dysfunctions in lysosomal enzyme β-glucocerebrosidase (GCase) play a crucial role in Gaucher and Parkinson's diseases. While pharmacological chaperones (PCs) stabilize GCase, the overall efficacy in restoring enzyme functionality is often abolished by their reluctance to dissociate from the enzyme once in lysosomes. To address this limitation, we developed pH-sensitive acetal functionalized iminosugars that hydrolyze under weakly acidic conditions, exploiting the pH difference between the endoplasmic reticulum and lysosomes to promote dissociation. Additionally, antioxidant moieties, derived from coniferyl aldehyde and vanillin, were incorporated to counteract oxidative stress, which is prevalent in Gaucher and Parkinson's diseases. The newly synthesized compounds 1-4 exhibit varying degrees of pH sensitivity and GCase stabilization in fibroblast ex vivo assays, with acetal 4 showing promising response, here validated both in lysates and in intact cells.

TL;DR: The stability of orthoester‐appended iminosugars was studied, and the loss of inhibitory activity with time in acid medium was demonstrated on cell lysates, and the ability to rescue GCase activity in the lysosomes as the result of a chaperoning effect was explored.