Treatment with certain epigenetic medicines may help compensate for a deficiency in the ABCD1 gene in patients with adrenoleukodystrophy (ALD), a study suggests.
Researchers found Merck’s epigenetic modifier Zolinza (vorinostat) helped increase the levels of the ABCD2 gene — which can compensate for the lack of the ABCD1 transporter — and eased brain inflammation in patients with cerebral ALD (CALD), the most severe form of the disease. However, the medicine produced toxic side effects, but the findings suggest the potential for other epigenetic medicines to treat ALD.
The study, “Vorinostat in the acute neuroinflammatory form of X-linked adrenoleukodystrophy,” was published in the journal Annals of Clinical and Translational Neurology.
ALD, also known as X-linked ALD (X-ALD), is caused by mutations in the ABCD1 gene, which contains the instructions to produce a transporter protein that allows fatty molecules, called very long‐chain fatty acids (VLCFAs), to be degraded. As a result of these mutations, the transporter fails to work properly, leading to the accumulation of fatty molecules in tissues, including the brain and spinal cord.
CALD affects around 60% of male X-ALD cases, and is characterized by fast destruction of brain white matter due to an inflammatory reaction. This uncontrolled inflammation causes brain lesions that arise as a disruption in the blood-brain barrier, a highly selective membrane that shields the central nervous system from general blood circulation.
The ABCD1 mutation affects predominantly immune cells called macrophages. The mutation impairs the cell’s metabolism and induces a constant pro-inflammatory state.
The ABCD2 gene codes for another receptor for VLCFAs that can also promote the breakdown of fatty molecules. Previous research suggests that the ABCD2 gene could compensate for ABCD1’s deficiency. However, the activity of the ABCD2 gene is markedly low in macrophages.
A team led by researchers at the Medical University of Vienna, in Austria, thus decided to investigate why the levels of the ABCD2 gene are so low in macrophages. They focused on the epigenetic profile of this gene. Epigenetics involves mechanisms that influence the activity of genes without altering the underlying DNA sequence.
The team found that a type of epigenetic alteration, called histone modification, particularly one called H3K36me3, was responsible for regulating the activity of ABCD2 gene expression in T-cells, a type of immune cell. Yet, this modification was nearly undetectable in macrophages.
This suggested that changing the level of histone modification in the ABCD2 gene could alter the gene’s activity in macrophages. The researchers, therefore, tested whether Merck’s Zolinza, a medicine whose mode of action is to alter histone modifications, could alter the levels of H3K36me3.
The researchers tested Zolinza in cells isolated from healthy controls and X-ALD patients. They saw that Zolinza treatment interfered with the transformation of monocytes into macrophages, indicating that the treatment could reduce the number of macrophages invading the brain. The treatment also led to an increased activity of the ABCD2 gene in macrophages, and improved the ability of macrophages to resolve a pro‐inflammatory status.
Supported by these results, the researchers treated three boys who had advanced CALD with Zolinza under a compassionate use program. The patients received the treatment for up to 80 days.
The maximum dose of Zolinza was limited by low blood platelet counts (thrombocytopenia), which was seen in all three patients. The dose for one patient was reduced. Treatment was stopped for the other two patients, who experienced severe gastrointestinal toxicity, and one also had hair loss.
Zolinza was found to have some beneficial effects in the boys, despite their disease progression. The patient who continued treatment showed normal levels of some biomarkers in the cerebrospinal fluid (the fluid surrounding the brain and spinal cord) after 80 days of treatment, and reduced lesions in the blood-brain barrier as shown by brain MRI, suggesting restored integrity of this barrier.
“However, a few months later an additional brain MRI revealed expansion of the demyelinating brain lesions … indicating ongoing [blood-brain barrier] breakdown,” the researchers wrote.
Overall, the results suggested that while Zolinza has a positive effect in maintaining the integrity of the blood-brain barrier, it “seems to require a disease state that is not too far advanced,” the researchers wrote. However, “it is not possible to predict a positive outcome even when treatment is started at an earlier disease stage,” they added.
Nonetheless, “the beneficial effects of [histone modification] inhibitors on macrophages in X‐ALD and the improvement of the blood‐[cerebrospinal fluid]/blood‐brain barrier are encouraging for future investigations,” the team noted.
Compared to Zolinza, “less toxic macrophage‐specific [histone modification] inhibitors might improve also the clinical state of X‐ALD patients,” the researchers said.
At the moment, more specific and selective inhibitors targeting histone modification are being tested for cancer, and inflammatory and neurodegenerative diseases, the team noted.
