A treatment increases survival by 50% in mice with Niemann-Pick type C, a rare disease that affects brain and liver

Researchers from the IIBB-CSIC and the IDIBAPS publish an article in the journal Redox Biology in which they propose an alternative treatment for Niemann-Pick disease type C, a rare lysosomal pathology that causes neurodegeneration and impaired liver function. With a compound that crosses the blood-brain barrier, it is possible to increase the survival of the mice by 50% and to improve the neurological and motor problems related to the disease. Dr. José C. Fernández-Checa, head of the IDIBAPS team on Mitochondrial regulation of cell death and steatohepatitis, and Dr. Carmen García-Ruiz, from the same team, are the coordinators of the study, which has been carried out in collaboration with researchers from France and Chile. The first author of the study is Sandra Torres, predoctoral researcher in Dr. Fernández-Checa’s lab.

Niemann-Pick disease type C (NPC) is a rare and serious disease, which usually appears after 15 years and causes neurological problems, motor problems and also affects the liver. In most cases, about 95%, the origin is found in mutations in the NPC1 gene. This causes the proteins involved in the trafficking of intracellular cholesterol not to work properly and makes that this lipid and others, such as ceramides or gangliosides, accumulate in the lysosomes and also in the mitochondria, two organelles inside the cell.

The accumulation of lipids in the mitochondria causes the antioxidant defense, particularly the mitochondrial glutathione (GSH), to be defective. "We wondered which impact would have the recovery of this mitochondrial defense on the development of the disease," explains Dr. Jose C. Fernández-Checa. To do this the researchers treated mice with the disease with glutathione precursors such as Acetylcysteine (NAC) or glutathione ester.

Mice with disease deficient in NPC1 have a short life, about 10-11 weeks. Treatment with GSH ester, but not with NAC, increased the level of mitochondrial glutathione, which increased survival by 50% and improved symptoms such as motor coordination and survival of Purkinje cells of the cerebellum, a type of neurons. In addition, the study shows that this treatment protects against oxidative stress in both brain and liver and improves mitochondrial function in the cerebellum, the most affected part of the brain by NPC, in which there is a massive death of neurons. This loss of neurons is responsible for motor problems. "With this compound, neuronal death is avoided in Niemann-Pick disease type C," says Dr. Fernández-Checa. "The treatment also has the advantage of being administered intraperitoneally, as it is able to cross the blood-brain barrier and reach the brain. Other alternative treatments that extract cholesterol from cell membranes, such as cyclodextrin, have shown some effect but are not able to reach the brain, "explains Dr. Carmen García-Ruiz.

The assay was also performed on fibroblasts, a cell type, from patients with the disease. Samples were obtained from 7 patients and it was found that when administering the glutathione ester increased the level of mitochondrial glutathione, in the same way that it happened in the mice. This turned into a greater survival of the cells in the in-vitro cultures.

"This study proposes, in short, an alternative treatment for NPC to those that already exist but that are not effective at all because they are not able to cross the blood brain barrier and reach the brain. Although the studies are preliminary, the good results obtained suggest that this compound can become a molecule of interest alone or in combination with other drugs for the treatment of Niemann-Pick type C disease, "concludes Dr. Fernández-Checa.

Article Reference:

Mitochondrial GSH replenishment as a potential therapeutic approach for Niemann Pick type C disease.

Torres S, Matías N, Baulies A, Nuñez S, Alarcon-Vila C, Martinez L, Nuño N, Fernandez A, Caballeria J, Levade T, Gonzalez-Franquesa A, Garcia-Rovés P, Balboa E, Zanlungo S, Fabrías G, Casas J, Enrich C, Garcia-Ruiz C, Fernández-Checa JC.

Redox Biol. 2016 Nov 20;11:60-72. doi: 10.1016/j.redox.2016.11.010.