Scientists have found that it may be possible for people with a rare genetic disorder to prevent fatal strokes by taking a common supplement. The genetic disorder is called hereditary cystatin C amyloid angiopathy (HCCAA); it's one of a group of disorders that involve the buildup of amyloid proteins on blood vessel walls in the central nervous system. Patients that carry a genetic mutation in the hCC gene called L68Q-hCC have HCCAA and may suffer multiple brain hemorrhages and strokes in their twenties, which can lead to dementia, paralysis, and death.
Amyloid deposits are present in many neurodegenerative diseases, including Alzheimer's, Parkinson's, and Huntington's, and this work may help provide some insight into improving treatments for those disorders as well. The study has been reported in Nature Communications.
"While this is a rare disease, most patients diagnosed with HCCAA die within five years of their first stroke, so there is an incredible need to study this genetic disorder and find effective treatment options," noted lead study author Hakon Hakonarson, M.D., Ph.D., Director of the Center for Applied Genomics at the Children's Hospital of Philadelphia (CHOP).
Scientists have been investigating whether drugs that can break down amyloid protein deposits will reduce toxicity to cells; amyloid-β (Aβ) species can be found in different states, some of which are thought to be more pathogenic than others.
In this work, the researchers developed a cell line that carried the L68Q mutant version of hCC. They looked for ways to disrupt the aggregation of the proteins without toxic side effects in these cells. One molecule, N-acetyl-cysteine (NAC), is sometimes used to break up lung mucus and protects against acetaminophen overdose-induced toxic liver damage; the researchers determined that NAC can break down the oligomers found in the mutant cell lines into monomers. That, in turn, helps prevent amyloid-producing proteins from forming and causing the deposits that have been linked to strokes.
The researchers took these findings to the patients carrying the L68Q-hCC variant, and performed skin biopsies on six of them. They determined that NAC reduced their L68Q-hCC levels from 50 to 90 percent. This gene variant may be targetable with this strategy. The researchers are working on a clinical trial now.
"Amyloids cannot precipitate without aggregating, so if we can prevent that aggregation with a drug that is already available, then we could make an incredible difference in the lives of these patients," Hakonarson said. "Additionally, since we already have genetic testing available to identify these patients, we could conceivably give this treatment early in life and potentially prevent that first stroke from ever occurring."