ECTRIMS eLearning

Beneficial effects of high-dose biotin (MD1003) in models of X-linked adrenoleukodystrophy
Author(s): ,
S. Fourcade
Affiliations:
IDIBELL; CIBERER U759, Barcelona, Spain
,
J. Parameswaran
Affiliations:
IDIBELL
,
L. Goicoechea
Affiliations:
IDIBELL
,
N. Launay
Affiliations:
IDIBELL; CIBERER U759, Barcelona, Spain
,
M. Ruiz
Affiliations:
IDIBELL; CIBERER U759, Barcelona, Spain
,
F. Sedel
Affiliations:
MedDay Pharmaceuticals, Paris, France
A. Pujol
Affiliations:
IDIBELL; CIBERER U759, Barcelona, Spain; ICREA, Barcelona, Spain
ECTRIMS Learn. Pujol A. 10/11/18; 228799; P956
Aurora Pujol
Aurora Pujol
Contributions
Abstract

Abstract: P956

Type: Poster Sessions

Abstract Category: Therapy - Others

Objective: Axonal degeneration is a main contributor to disability in progressive neurodegenerative diseases such as multiple sclerosis or adrenoleukodystrophy (X-ALD), in which redox homeostasis, bioenergetic failure and/or inflammation are often identified as pathogenic factors. X-ALD is a monogenic neurometabolic disorder caused by inactivation of the peroxisomal transporter of very long-chain fatty acids ABCD1. In mice, ABCD1 loss causes late onset, progressive axonal degeneration in the spinal cord's corticospinal tracts in association with locomotor disability resembling the most common phenotype in patients, adrenomyeloneuropathy.
Methods: Here we are using models of X-ALD to: i) investigate if high oral doses of biotin (MD1003) are able to improve the clinical signs of the disease (axonal degeneration and locomotor deficits), and ii) elucidate by which molecular and biochemical mechanisms it operates.
Results: Our results indicate that treatment with MD1003 during 4 months normalizes ATP and mtDNA levels in the spinal cords of Abcd1-null mice. This induction of mtDNA is correlated to an increase in mitochondrial biogenesis factors and in the expression of some enzymes involved in glycolysis. Most importantly, the treatment halted the late-onset axonopathy in spinal cords of Abcd1-/Abcd2-/- mice, and the associated locomotor disability as assessed by treadmill and bar-cross tests. In human fibroblasts from patients with X-ALD, MD1003 treatment (50-500 µM) was able to abolish reactive oxygen species (ROS) generated by an excess of a very long-chain fatty acid C26:0 that accumulates in patients.
Conclusion: These results show preclinical safety and efficacy in mouse models of X-ALD and reveal novel molecular mechanisms of action of MD1003 in the prevention of neurodegeneration. Future studies should address the effects of this drug on other axonopathies in which bioenergetic dysfunction and oxidative stress are contributing factors.
Disclosure: Conflict of interest:
The study has been funded by MedDay Pharmaceuticals
Frédéric Sedel is an employee of MedDay.
Stéphane Fourcade, Janani Parameswaran and Leire Goicoechea are employees of IDIBELL.
Nathalie Launay and Montserrat Ruiz are employees of CIBERER.
Aurora Pujol is an employee of ICREA.
Authors should indicate their presentation preference:
Poster presentation only

Abstract: P956

Type: Poster Sessions

Abstract Category: Therapy - Others

Objective: Axonal degeneration is a main contributor to disability in progressive neurodegenerative diseases such as multiple sclerosis or adrenoleukodystrophy (X-ALD), in which redox homeostasis, bioenergetic failure and/or inflammation are often identified as pathogenic factors. X-ALD is a monogenic neurometabolic disorder caused by inactivation of the peroxisomal transporter of very long-chain fatty acids ABCD1. In mice, ABCD1 loss causes late onset, progressive axonal degeneration in the spinal cord's corticospinal tracts in association with locomotor disability resembling the most common phenotype in patients, adrenomyeloneuropathy.
Methods: Here we are using models of X-ALD to: i) investigate if high oral doses of biotin (MD1003) are able to improve the clinical signs of the disease (axonal degeneration and locomotor deficits), and ii) elucidate by which molecular and biochemical mechanisms it operates.
Results: Our results indicate that treatment with MD1003 during 4 months normalizes ATP and mtDNA levels in the spinal cords of Abcd1-null mice. This induction of mtDNA is correlated to an increase in mitochondrial biogenesis factors and in the expression of some enzymes involved in glycolysis. Most importantly, the treatment halted the late-onset axonopathy in spinal cords of Abcd1-/Abcd2-/- mice, and the associated locomotor disability as assessed by treadmill and bar-cross tests. In human fibroblasts from patients with X-ALD, MD1003 treatment (50-500 µM) was able to abolish reactive oxygen species (ROS) generated by an excess of a very long-chain fatty acid C26:0 that accumulates in patients.
Conclusion: These results show preclinical safety and efficacy in mouse models of X-ALD and reveal novel molecular mechanisms of action of MD1003 in the prevention of neurodegeneration. Future studies should address the effects of this drug on other axonopathies in which bioenergetic dysfunction and oxidative stress are contributing factors.
Disclosure: Conflict of interest:
The study has been funded by MedDay Pharmaceuticals
Frédéric Sedel is an employee of MedDay.
Stéphane Fourcade, Janani Parameswaran and Leire Goicoechea are employees of IDIBELL.
Nathalie Launay and Montserrat Ruiz are employees of CIBERER.
Aurora Pujol is an employee of ICREA.
Authors should indicate their presentation preference:
Poster presentation only

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