New research indicates that N-acetylcysteine (NAC) – a medicine widely used to treat paracetamol overdose and dietary supplement with anti-inflammatory and antioxidant properties – holds promise in treating hereditary cystatin C amyloid angiopathy (HCCAA) – a rare form of familial dementia found mostly in Icelandic people.
Icelandic drug discovery and development company Arctic Therapeutics (ATx) has published research which informs a possible therapeutic strategy to treat a rare form of familial dementia.
The non-randomised clinical trial, details a new treatment approach for HCCAA, a rare and fatal genetic brain disorder that primarily affects young Icelandic adults, with the disease process beginning in childhood.
The research provides insights into the potential of N-acetylcysteine (NAC) as a treatment for HCCAA, a disease with no currently approved therapeutic options. The study highlights how NAC may reduce disease-associated biomarkers and slow disease progression.
The study is the first phase 2a clinical trial to assess the safety and therapeutic potential of high-dose NAC in patients carrying the L68Q-CST3 sequence variation of HCCAA. Results indicate that NAC is well tolerated, reduces disease specific biomarkers and stabilises disease progression, suggesting NAC may offer a preventative strategy against HCCAA.
These findings could accelerate the development of preventative therapies for individuals at risk of HCCAA and other forms of CAAs.
“These promising results provide hope to HCCAA patients and their families,” Dr Ásbjörg Ósk Snorradóttir, lead author of the study explained.
Senior author, Dr. Hákon Hákonarson, director of the Center for Applied Genomics at the Children’s Hospital of Philadelphia and founder of Arctic Therapeutics added: “This study provides the first clinical evidence that NAC, by breaking disulfide bonds and other aberrant molecular interactions, can disrupt cystatin C oligomers and prevent amyloid aggregation that ultimately accumulates in brain vessels.
“By targeting the root biochemical process behind HCCAA pathology, NAC may ultimately offer a novel disease-modifying approach, not only for this devastating condition, but potentially for other forms of CAAs and protein aggregation disorders where toxic oligomers are central to disease progression.”
The study assessed safety and tolerability, finding that NAC was well tolerated, with no drug-related severe adverse events (five participants experienced cerebral haemorrhages, but none resulted in permanent neurological damage); biomarker reduction, finding significant reductions in collagen IV, fibronectin, vimentin, and SMAD levels – key indicators of disease progression; plasma and skin biomarker changes, finding that NAC increased glutathione levels, a protective antioxidant, and reduce high-molecular-weight cystatin C aggregates, which are linked to amyloid buildup in the brain; and, cognitive stability, finding no measurable decline in cognitive function during the study period.
Building on these findings, as well as internal in-vitro data that demonstrates that NAC-amide (NACA) has more than 10-fold higher potency in preventing or dispersing amyloid complex aggregates than NAC and increased ability to penetrate the blood brain barrier and get into cells involved in the disease pathogenesis, ATx has launched a European Medicines Agency-approved registration study to monitor safety, tolerability, and efficacy using NACA in patients with HCCAA.
