MD1003, a high-dose biotin, rescued locomotor (movement) activity and halted axon (nerve fiber) degeneration in two mouse models of X-linked adrenoleukodystrophy (ALD), including one with more severe and early disease onset, a study shows.
The results were presented at the 2019 American Academy of Neurology (AAN) Annual Meeting (May 4-10), by Stéphane Fourcade, researcher at IDIBELL, Barcelona, Spain, in a poster titled “Beneficial Effects of High-dose Biotin (MD1003) in Models of X-linked adrenoleukodystrophy.”
Biotin is a form of vitamin B, and it plays an important role in energy production within cells. MD1003 is a highly concentrated oral formulation of biotin that acts on neurons’ metabolism to minimize the loss and promote the repair of myelin — the protective, fat-rich substance that wraps around axons. Myelin is progressively destroyed in diseases such as multiple sclerosis and ALD, causing disability.
In the study, researchers at IDIBELL and Medday Pharmaceuticals used two mouse models of X-ALD to investigate whether MD1003 can halt axon degeneration and locomotor deficits. The team also investigated the molecular mechanisms by which MD1003 may exert its effects.
Researchers used a mouse model generated by deleting the ABCD1 gene, which is the cause of X-ALD when mutated. ABCD2 is another gene with a very similar function to ABCD1 that, upon absence of ABCD1, may try to compensate for its effects.
As a result, to analyze the effects of MD1003 on locomotor behavior and axonal degeneration, researchers used another mouse model that was genetically modified to lack both ABCD1 and ABCD2 genes, called a double knockout (KO) mouse, known to have a more severe disease and earlier onset than the single ABCD1 KO mice.
Researchers mixed MD1003 with the animals’ diet so that the final dose would be 55 milligrams (mg)/kg/day, the equivalent of a 300 mg daily dose in humans.
The ABCD1 KO mice were given MD1003 for three months. Researchers then assessed the impact of the therapy on the production of mitochondria — the cell’s powerhouses, where energy is produced — and on key factors for neurons’ function.
The analysis at 13 months showed that MD1003 rescued mitochondria function and normalized energy production in the ABCD1 KO mice, with the animals reaching similar loads of mitochondrial DNA as those seen in normal mice. The treatment thus seems to prevent the energy failure of the ABCD1 KO mice.
The activity of genes controlling the production of mitochondria, such as the PGC1-alpha gene, is decreased in the ABCD1 KO mice. Treatment with MD1003 also rescued gene activity to the levels seen in normal mice.
Studies in vitro (in a lab setting) with X-ALD patients’ cells, called fibroblasts, also showed that MD1003 neutralizes the release of reactive oxygen species, which promote nerve cell damage and myelin degeneration.
“These results encouraged [us] to treat the animals for a longer time to assess the axonal degeneration and the locomotor activities,” Fourcade told Adrenoleukodystrophy News.
For these analyses, the team used the double KO mice, in which they measured the changes in locomotor function by assessing the animals’ performance on a treadmill, balance on a wooden bar, and hindlimb clasping. Mice were treated for six months and the analyses were done after 18 months.
Researchers also looked at how treatment with MD1003 affected axonal degeneration in the treated animals compared with that of controls.
They first confirmed that compared to normal mice, the double KO mice performed significantly poorly on the treadmill and had less balance. After six months of treatment with MD1003, the animals recovered both the locomotor functions and balance to the levels seen in normal mice.
Mice treated with MD1003 also recovered hindlimb clasping, which was significantly impaired upon deletion of the ABCD1/ABCD2 genes. Loss of hindlimb clasping is a marker of disease progression in a number of mouse models of neurodegeneration.
Analysis of axons in the double KO mice confirmed that treatment with MD1003 significantly reduced loss of axons, as shown by a significant decrease in markers of axonal damage, namely the protein synaptophysin and the amyloid precursor protein.
Moreover, researchers saw once again that MD1003 enhanced mitochondria production as seen previously using the ABCD1 KO mice.
Based on the results, “we think this treatment could be useful for adrenomyeloneuropathy patients, who show similar impairments to the mouse model,” Fourcade said.
The researchers stated, “Future studies should address the effects of this drug on other axonopathies.”
Of note, MD1003 is currently being tested as a potential therapy for progressive multiple sclerosis patients. Patients receive MD1003 as a 100 mg capsule three times a day (total daily dose of 300 mg).