High dose pharmaceutical grade biotin (MD1003) protects axons in a TMEV-induced mouse model of progressive multiple sclerosis
ECTRIMS Online Library. Warrington A. 09/12/19; 278209; P1007
Arthur Warrington
Arthur Warrington
Contributions
Abstract

Abstract: P1007

Type: Poster Sessions

Abstract Category: Therapy - Neuroprotection and Repair

A. Warrington1, M. Perdomini2, D. Bernard2, M. Rodriguez1

1Neurology and Neurosurgery, Mayo Clinic, Rochester, MN, United States, 2MedDay Pharmaceuticals SA, Paris, France

Introduction: High dose Pharmaceutical grade Biotin (MD1003), administered orally at 100 mg three times a day, is under investigation as a treatment for progressive multiple sclerosis (MS). Biotin is a co-factor required for energy production and fatty acid synthesis important for myelin membrane production. The repair of myelin and protection of axons are important therapeutic goals in progressive MS. Intracerebral infection of mice with Theiler's murine encephalomyelitis virus (TMEV) results in strain-dependent disease: inflammatory demyelination in the spinal cord, a model of MS, and hippocampal lesions associated with seizures, a model of acquired epilepsy following infection (DePaula-Silva et al., 2017).
Objectives: Determine whether oral administration of MD1003 beginning at the onset of spinal cord demyelination preserves spinal cord axons, brain pathology, or neurological function in SJL mice infected with TMEV.
Methods: SJL mice infected with TMEV were treated with 100, 300, or 600 mg/day human equivalent dose (HED) of MD1003 for 29 weeks starting at 45 days post infection (DPI). Neurological function was evaluated before and during treatment. Upon sacrifice, the extent of spinal cord demyelination/remyelination and preservation of myelinated axons by caliber was assessed. A blinded systematic analysis of the pathology of the spinal cord, cortex, corpus callosum, hippocampus, brain stem, striatum, and cerebellum was performed using a five-point scale (0: no pathology; to 4: necrosis).
Results: A dose-dependent preservation of hanging wire performance (a measure of fatigue and strength) and a preservation of thoracic level myelinated spinal cord axons were observed in the MD1003-treated groups, but not in the controls. Hippocampal lesions, present in the control group and lower dose MD1003 treatment groups, were absent in the highest dose group of 600 mg/day HED MD1003 treated mice (n=15 per group, P=0.05).
Conclusions: MD1003 treatment preserved myelinated spinal cord axons and function in a model of chronic inflammatory spinal cord demyelination, supporting the hypothesis that MD1003 acts by protecting neurons and axons. Of interest, mice treated with the highest tested dose of MD1003 did not contain lesions in the hippocampus, a neurogenic region of the adult rodent brain.
Disclosure: Study supported by: MedDay Pharmaceuticals (ref. COM-389-001).
AE Warrington received hospitality from Medday Pharmaceuticals SA for presentation during meetings.
M Rodriguez received hospitality from Medday Pharmaceuticals SA for presentation during meetings.
M Perdomini is an employee of MedDay Pharmaceuticals.
D Bernard is an employee of MedDay Pharmaceuticals.

Abstract: P1007

Type: Poster Sessions

Abstract Category: Therapy - Neuroprotection and Repair

A. Warrington1, M. Perdomini2, D. Bernard2, M. Rodriguez1

1Neurology and Neurosurgery, Mayo Clinic, Rochester, MN, United States, 2MedDay Pharmaceuticals SA, Paris, France

Introduction: High dose Pharmaceutical grade Biotin (MD1003), administered orally at 100 mg three times a day, is under investigation as a treatment for progressive multiple sclerosis (MS). Biotin is a co-factor required for energy production and fatty acid synthesis important for myelin membrane production. The repair of myelin and protection of axons are important therapeutic goals in progressive MS. Intracerebral infection of mice with Theiler's murine encephalomyelitis virus (TMEV) results in strain-dependent disease: inflammatory demyelination in the spinal cord, a model of MS, and hippocampal lesions associated with seizures, a model of acquired epilepsy following infection (DePaula-Silva et al., 2017).
Objectives: Determine whether oral administration of MD1003 beginning at the onset of spinal cord demyelination preserves spinal cord axons, brain pathology, or neurological function in SJL mice infected with TMEV.
Methods: SJL mice infected with TMEV were treated with 100, 300, or 600 mg/day human equivalent dose (HED) of MD1003 for 29 weeks starting at 45 days post infection (DPI). Neurological function was evaluated before and during treatment. Upon sacrifice, the extent of spinal cord demyelination/remyelination and preservation of myelinated axons by caliber was assessed. A blinded systematic analysis of the pathology of the spinal cord, cortex, corpus callosum, hippocampus, brain stem, striatum, and cerebellum was performed using a five-point scale (0: no pathology; to 4: necrosis).
Results: A dose-dependent preservation of hanging wire performance (a measure of fatigue and strength) and a preservation of thoracic level myelinated spinal cord axons were observed in the MD1003-treated groups, but not in the controls. Hippocampal lesions, present in the control group and lower dose MD1003 treatment groups, were absent in the highest dose group of 600 mg/day HED MD1003 treated mice (n=15 per group, P=0.05).
Conclusions: MD1003 treatment preserved myelinated spinal cord axons and function in a model of chronic inflammatory spinal cord demyelination, supporting the hypothesis that MD1003 acts by protecting neurons and axons. Of interest, mice treated with the highest tested dose of MD1003 did not contain lesions in the hippocampus, a neurogenic region of the adult rodent brain.
Disclosure: Study supported by: MedDay Pharmaceuticals (ref. COM-389-001).
AE Warrington received hospitality from Medday Pharmaceuticals SA for presentation during meetings.
M Rodriguez received hospitality from Medday Pharmaceuticals SA for presentation during meetings.
M Perdomini is an employee of MedDay Pharmaceuticals.
D Bernard is an employee of MedDay Pharmaceuticals.

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