Targeting and Treatment of Lysosome Storage Diseases
Similar to the way food is digested in our stomach, cells break down harmful waste, viruses, bacteria, and other cellular components using organelles called lysosomes. Defects in this process results in storage of excess waste that is detrimental to the cell. Lysosomal storage diseases (LSDs) are a large group of over 50 rare inherited metabolic disorders due to improper lysosomal function. For example, Niemann-Pick Disease (NPD) can be due to deficiency of enzymes that metabolize lipids or cholesterol, depending on the type of the disease. According to the National Niemann-Pick Disease Foundation, over 1700 people are diagnosed with the disease and it is believed that many more patients have the disease, but are often misdiagnosed. LSDs primarily affect children, often causing death at a young age. NPD symptoms include enlarged livers and spleens, respiratory problems and heart disease, or even severe neurological disease that leads to early death. Other symptoms of LSD can vary depending on the cause, and can include developmental delay, movement disorders, seizures, dementia, deafness and/or blindness. There are currently no cures for LSDs and most treatments are directed towards alleviating symptoms of the disorder. It is, therefore, important to understand the mechanism of these severe diseases and identify small molecules that could reduce lysosomal storage and be used as potential therapeutics for LSDs.
A Potent Small-Molecule Agonist of TRPML1
Mucolipin transient receptor potential channel 1 (TRPML1) is the principle Ca2+ channel in the lysosome, which is believed to play a critical role in lysosomal storage diseases (LSDs) and severe neurodegenerative diseases. Researchers have demonstrated that TRPML1-mediated lysosomal calcium (Ca2+) release is dramatically reduced in Niemann-Pick types A and C (NPA and NPC, respectively) disease cells, a type of LSD. In NPC cells, increasing TRPML1’s activity was found to be capable of correcting cell trafficking defects. ML-SA1, a potent small-molecule activator of TRPML1 was shown to increase the activity of TRPML1-mediated Ca2+ release from lysosomes in normal cells. ML-SA1-induced lysosomal Ca2+ release was reduced in NPC1-/- and NPA cells. It was also shown that ML-SA1 can correct the late endosome and lysosome (LEL)-to-Golgi trafficking defects and can reduce cholesterol accumulation in NPC cells. These results suggest that ML-SA1 can be used to reverse the adverse effects of diseases caused by defective TRPML1.
Applications and Advantages
- Lysosomal storage disease treatment
- Chemical biology tool
- First therapeutic treatment for lysosomal storage diseases
- Potent TRPML1 agonist