Science researchers have discovered a new “cellular pathway” in type-2 Gaucher disease, a genetic disorder that especially affects Jews of Ashkenazi origin. They believe their findings, just published in Nature Medicine, may lead to a new way of treating it.
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Gaucher is caused by a defect in a specific enzyme needed to break down a lipid (fatty substance) called glucocerebroside.
This results in the accumulation of glucocerebroside in various cells and organs, especially in the liver, spleen and bones, which prevents them from working properly. The disease can appear at any age, but it often occurs in young childhood.
There are three subtypes of the disease. The most common form – type 1 – is characterized by, among other symptoms, swelling and enlargement of the spleen and liver, along with lung and bone problems. These symptoms can also affect individuals with type-2 and type-3 Gaucher disease, but these forms of the disease also affect the brain. Type 2 – the most severe form – causes extensive brain damage and death before two years of age, while type 3 affects the brain more progressively, with patients often living into their early teens and adulthood.
Type 1 can be treated with injections of an intact version of the enzyme that breaks down glucocerebroside – which costs about $200,000 per patient per year – but the enzyme is unable to get into the brain, making it ineffective in treating the neurological symptoms of types 2 and 3.
Scientists at Weizmann found a connection between a protein called RIP3 and cell death and inflammatory processes.
Dr. Einat Vitner and master’s degree student Ran Salomon, in the lab of Prof.
Tony Futerman of the biological chemistry department, wondered whether the effects of Gaucher disease were tied to RIP3.
To find out, they induced Gaucher disease in mice possessing the RIP3 protein, as well as in mice lacking the protein. In mice without RIP3, they showed not only a significant improvement in motor coordination and brain pathology, but also improved liver and spleen function.
Their lifespan was also increased from approximately 35 days to more than 170 days.
“These results are exciting, as they suggest a plausible new target for therapeutic intervention for all types of Gaucher disease; they have the potential, in the future, to greatly improve the patients’ quality of life,” Vitner said.
“If successful, the new target could be used as either a complementary or alternative therapy for Gaucher disease, and with RIP3 proving to be a ‘hot’ cellular pathway in various pathologies, these results may also have implications in other neurodegenerative diseases, including related diseases such as Krabbe disease, and potentially other devastating brain diseases,” Futerman said.
Greg and Deborah Macres, whose son Gregory died of Gaucher at the age of four, established the nonprofit Children’s Gaucher Research Fund in 1999. It has been instrumental in enabling research aimed at finding a cure for type-2 and type-3 Gaucher, such as that carried out in Futerman’s lab, and for providing support to families of children who battle this disease. The Macres family said they were grateful for the new development so that “one day, a physician can tell the anxious parents of a sick child – “Don’t worry; we have a cure.”