A thyromimetic drug accelerates remyelination in vivo: a small molecule approach to promoting repair in multiple sclerosis
Author(s): ,
D. Bourdette
Affiliations:
Oregon Health & Science University, Portland, OR, United States
,
M. Hartley
Affiliations:
Oregon Health & Science University, Portland, OR, United States
,
P. Chaudhary
Affiliations:
Oregon Health & Science University, Portland, OR, United States
,
G. Marracci
Affiliations:
Oregon Health & Science University, Portland, OR, United States
T. Scanlan
Affiliations:
Oregon Health & Science University, Portland, OR, United States
ECTRIMS Online Library. Bourdette D. 10/08/15; 115626; 787
Dennis Bourdette
Dennis Bourdette
Contributions
Abstract
Abstract: P583

Type: Poster

Abstract Category: Neurorepair

Background and goal: Chronic demyelination contributes to permanent disability (MS) and progressive axonal degeneration in multiple sclerosis (MS). The thyroid hormone, triiodothyronine (T3), accelerates differentiation of oligodendrocyte precursor cells (OPC) into mature oligodendrocytes (OL). T3 stimulates remyelination in the cuprizone model and experimental autoimmune encephalomyelitis. However, chronic T3 therapy is not a practical treatment for MS because of the adverse effects on heart, bone, and skeletal muscle of hyperthyroidism.

Sobetirome is a thyromimetic drug devoid of cardiac effects that has been studied in phase 1 trials for lowering cholesterol. We determined whether sobetirome could accelerate remyelination in the lysolecithin model to assess the potential of thyromimetics for the treatment of MS.

Methods and results: We stereotactically injected lysolecithin (2%) into the corpus callosum of C57BL/6 mice. Five days later we randomized mice for histology or daily injections of vehicle, T3 (0.4 mg/kg) or sobetirome (5 mg/kg). Treated mice were processed for histology 10, 12 and 15 days after lysolecithin injection. Serial sections through the lesion were stained for myelin with Black Gold. Sections were evaluated blinded to treatment. Area of demyelination in each section was determined and a volume of demyelination determined.

At day 5 mean volume of the demyelination at the injection site was 0.062mm^3. In mice receiving vehicle mean of volume of demyelination rose on day 10 and 12 to 0.067 and 0.082 and fell to 0.022 on day 15. In mice receiving T3, volume of demyelination at days 10, 12 and 15 were 0.070, 0.019 and 0.016, respectively. In mice receiving sobetirome, the volume of demyelination on days 10, 12 and 15 were 0.074, 0.055 and 0.028, respectively. The volumes of demyelination on day 12 for mice receiving T3 and sobetirome versus vehicle were significantly lower (p=0.0214). The effect of treatment on the cell populations in the lesion (OPCs, OLs, and microglia) analyzed by immunofluorescence and the presence of thinly remyelinated axons measured by electron microscopy will be presented.

Conclusion: This is the first demonstration of the ability of a thyromimetic drug to accelerate remyelination in vivo. Thyromimetics represent a class of small molecule drugs that might stimulate remyelination in MS with a better safety profile than thyroid hormone.

Disclosure:

Dr. Bourdette is a co-inventor of a licensed pending patent application claiming the use of sobetirome for the treatment of multiple sclerosis and received research funding from the Laura Fund for Innovation in MS Research.

Dr. Hartley is a co-inventor of a licensed pending patent application claiming the use of sobetirome for the treatment of multiple sclerosis.

Dr. Chaudhary is a co-inventor of a licensed pending patent application claiming the use of sobetirome for the treatment of multiple sclerosis.

Dr. Marracci is a co-inventor of a licensed pending patent application claiming the use of sobetirome for the treatment of multiple sclerosis.

Dr. Scanlan is a co-inventor of a licensed pending patent application claiming the use of sobetirome for the treatment of multiple sclerosis and received research funding from the Laura Fund for Innovation in MS Research.
Abstract: P583

Type: Poster

Abstract Category: Neurorepair

Background and goal: Chronic demyelination contributes to permanent disability (MS) and progressive axonal degeneration in multiple sclerosis (MS). The thyroid hormone, triiodothyronine (T3), accelerates differentiation of oligodendrocyte precursor cells (OPC) into mature oligodendrocytes (OL). T3 stimulates remyelination in the cuprizone model and experimental autoimmune encephalomyelitis. However, chronic T3 therapy is not a practical treatment for MS because of the adverse effects on heart, bone, and skeletal muscle of hyperthyroidism.

Sobetirome is a thyromimetic drug devoid of cardiac effects that has been studied in phase 1 trials for lowering cholesterol. We determined whether sobetirome could accelerate remyelination in the lysolecithin model to assess the potential of thyromimetics for the treatment of MS.

Methods and results: We stereotactically injected lysolecithin (2%) into the corpus callosum of C57BL/6 mice. Five days later we randomized mice for histology or daily injections of vehicle, T3 (0.4 mg/kg) or sobetirome (5 mg/kg). Treated mice were processed for histology 10, 12 and 15 days after lysolecithin injection. Serial sections through the lesion were stained for myelin with Black Gold. Sections were evaluated blinded to treatment. Area of demyelination in each section was determined and a volume of demyelination determined.

At day 5 mean volume of the demyelination at the injection site was 0.062mm^3. In mice receiving vehicle mean of volume of demyelination rose on day 10 and 12 to 0.067 and 0.082 and fell to 0.022 on day 15. In mice receiving T3, volume of demyelination at days 10, 12 and 15 were 0.070, 0.019 and 0.016, respectively. In mice receiving sobetirome, the volume of demyelination on days 10, 12 and 15 were 0.074, 0.055 and 0.028, respectively. The volumes of demyelination on day 12 for mice receiving T3 and sobetirome versus vehicle were significantly lower (p=0.0214). The effect of treatment on the cell populations in the lesion (OPCs, OLs, and microglia) analyzed by immunofluorescence and the presence of thinly remyelinated axons measured by electron microscopy will be presented.

Conclusion: This is the first demonstration of the ability of a thyromimetic drug to accelerate remyelination in vivo. Thyromimetics represent a class of small molecule drugs that might stimulate remyelination in MS with a better safety profile than thyroid hormone.

Disclosure:

Dr. Bourdette is a co-inventor of a licensed pending patent application claiming the use of sobetirome for the treatment of multiple sclerosis and received research funding from the Laura Fund for Innovation in MS Research.

Dr. Hartley is a co-inventor of a licensed pending patent application claiming the use of sobetirome for the treatment of multiple sclerosis.

Dr. Chaudhary is a co-inventor of a licensed pending patent application claiming the use of sobetirome for the treatment of multiple sclerosis.

Dr. Marracci is a co-inventor of a licensed pending patent application claiming the use of sobetirome for the treatment of multiple sclerosis.

Dr. Scanlan is a co-inventor of a licensed pending patent application claiming the use of sobetirome for the treatment of multiple sclerosis and received research funding from the Laura Fund for Innovation in MS Research.

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