Category: Cerebral adrenoleukodystrophy (cALD)

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 €

X-linked adrenoleukodystrophy (ALD) is a severe disease, ranging from the fatal cerebral inflammatory demyelinating form affecting boys (cALD) to the peripheral dying back axonopathy that affects adults (AMN). There are no effective therapies for AMN, and the cause of cALD is poorly understood.

The goal is to develop, validate, and use for treatment discovery, a new model of ALD. To accomplish this, the group will use the small genetic vertebrate model zebrafish, which has low costs and the ability to perform high-throughput screens that are unfeasible in other vertebrate systems. Zebrafish have the same genes as humans, including ABCD1, the gene responsible for ALD. The data shows that mutations in zebrafish ABCD1 cause ALD in zebrafish. The team is using the ALD zebrafish model to validate a new potential treatment for ALD, to understand this drug’s mechanism, and to understand the cause of cALD.

Project financed by ELA up to: 98 841 €