δ-Tocopherol reduces lipid accumulation in Niemann-Pick type C1 and Wolman cholesterol storage disorders.

Abstract

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Phenotypic screens as a renewed approach for drug discovery

“…Generally, a characteristic associated with the disease is exploited to develop a cell-based assay for a modern phenotypic screen (Figure 2B). Compounds are then screened in the phenotypic assay to identify active lead compounds that ameliorate the disease phenotype, exemplified by selectively killing cancer cells [19], eliminating pathogens in culture [20], or reducing lysosomal cholesterol accumulation in Niemann Pick disease type C patient cells [21]. …”

“…For example, expression of long CAG trinucleotide repeats in the mutant HTT gene in Huntington’s disease is cytotoxic and results in cell death, which can be detected by a cell viability assay [43,50]. In Niemann Pick disease type C, lysosomal cholesterol accumulation in patient cells is a characteristic disease phenotype that can be measured by a filipin staining assay [21,51]. …”

Regulation of TRPML1 function

“…This was also found to be the case for the primary sphingomyelin storage disorder Niemann-Pick type A. However, the authors found no difference in lysosomal Ca 2 + content between wild-type and NPC1 null cells, despite this being widely reported [38][39][40][41]. The authors found that treating NPC1 null cells with MLSA1 led to an improvement in phenotypes.…”

Lysosomes and Nanotherapeutics: Diseases, Treatments, and Side Effects

“…104 Lysosomal exocytosis has also been documented in MSD and MPS type IIIA via overexpression of transcription factor EB (TFEB), 105 or by using δ-tocopherol, as shown for NPC and Wolman diseases. 106 Moreover, δ-tocopherol has been shown to reduce lipid accumulation in LSD cell models of Batten, Fabry, Farber, Sanfilippo type B, Tay-Sachs, and Niemann-Pick disease type A. 106 Although certainly valuable, most these approaches are suboptimal, particularly for neurological symptoms.…”

“…106 Moreover, δ-tocopherol has been shown to reduce lipid accumulation in LSD cell models of Batten, Fabry, Farber, Sanfilippo type B, Tay-Sachs, and Niemann-Pick disease type A. 106 Although certainly valuable, most these approaches are suboptimal, particularly for neurological symptoms. Hence, there is a compelling need for approaches to more effectively treat these diseases.…”