X-linked adrenoleukodystrophy (X-ALD) is the most common leukodystrophy with the adult-onset peripheral nerve disease adrenomyeloneuropathy being the underlying core syndrom. However, the majority of patients also develop fatal inflammatory brain demyelination, termed cerebral ALD (CALD). Hematopoietic stem cell transplantation (HSCT) is an established treatment that is able to halt CALD in both childhood and adult patients and is currently, next to hematopoietic stem cell gene therapy (HSCGT), the only available life-saving intervention for CALD patients. Unfortunately, both HSCT and HSCGT are only effective during a narrow therapeutic window at the beginning of CALD, thus excluding patients with advanced CALD from these treatments. We propose to validate pharmacological compounds known as histone deacetylase (HDAC) inhibitors, which are well-tolerated anti-cancer drugs, as a means to stop the macrophage-related inflammatory responses, with a potential ultimate application for advanced CALD patients. We will compare and evaluate the dosage and ability of three different HDAC inhibitors to reverse functional abnormalities like pro-inflammatory activation and accumulation of very long-chain fatty acids in macrophages isolated from the blood of X-ALD patients. X-ALD macrophages are the immune cells most affected by X-ALD and thus, are therapeutic targets. We think that if HDAC inhibitors prove to be effective in X-ALD macrophages, these drugs might delay, ameliorate or even halt the cerebral inflammation in patients with CALD.

Project financed by ELA up to: 66 315 €