Abstract Details

Title Thyromimetics improve disease endpoints and modulate potential target engagement biomarkers in rodent models of ALD and MS

Topic Multiple Sclerosis

Presentation(s) P3 - Poster Session 3 (5:30 PM-6:30 PM)

Poster/Presentation
Number 12-011

Background

Thyroid hormone has pleiotropic effects in vivo which may be harnessed for therapeutic treatment of neurodegenerative disorders, including X-linked Adrenoleukodystrophy (ALD) and Multiple Sclerosis (MS). Novel thyromimetic prodrugs are being developed where brain delivery is enhanced through specific cleavage by fatty acid amide hydrolase (FAAH). Using this prodrug approach, these drugs demonstrate >30-fold enrichment of functional delivery of thyromimetics to the brain. Studies described here link efficacy endpoints with potential biomarkers of target engagement and remyelination.

Objective

To investigate preclinical efficacy and identify potential biomarkers of CNS-delivered thyromimetics in disease models of remyelination relevant to neurodegeneration.

Design/Methods

In a model of ALD using Abcd1 (-/y) mice, brain and plasma very long chain fatty acids (VLCFA), mRNA and microRNA expression profiles were determined after ABX-002 administration. In a model of demyelination in MS using cuprizone-treated rats, 24-hydroxycholesterol (24-OHC, the brain metabolite of cholesterol and an indirect measure of myelin turnover) and mRNA expression profiles were determined.

Results

ABX-002 decreased brain and plasma VLCFA content in Abcd1 (-/y) mice. In the rat cuprizone model, thyromimetic treatment increased the fractional synthesis of 24-OHC in brain, and plasma, suggesting an increased rate of myelin synthesis and highlights a potential peripheral biomarker of remyelination. Transcriptomic profiling of the brains of both models demonstrated increased expression of known T3-responsive genes and identified novel T3-responsive microRNAs that respond to thyromimetic treatment. These microRNAs may also be present in biofluids, such as blood or CSF, whereby they could be utilized as target engagement biomarkers.

Conclusions

CNS-directed thyromimetics have potential as treatments for neurodegenerative diseases. Small RNA profiling identified novel T3-responsive microRNAs that track with efficacy endpoints after drug treatment and can potentially be used as biomarkers.

Authors/Disclosures
Michaelanne B. Woerner, PhD (Autobahn Therapeutics) PRESENTER	Michaelanne Woerner has received personal compensation for serving as an employee of Autobahn Therapeutics. Michaelanne Woerner has stock in Autobahn Therapuetics.
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
Rohan Gandhi, PhD (Autobahn Therapeutics)	Dr. Gandhi has received personal compensation for serving as an employee of Autobahn Therapeutics. Dr. Gandhi has stock in Autobahn Therapeutics.
Chan Beals	Chan Beals has received personal compensation for serving as an employee of Autobahn Therapeutics.
	No disclosure on file
Deidre MacKenna, PhD (Autobahn Therapeutics)	Deidre MacKenna has received personal compensation for serving as an employee of Autobahn Therapeutics. Deidre MacKenna has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for PharmAkea Therapeutics. Deidre MacKenna has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Regulus Therapeutics. Deidre MacKenna has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Pacific Rim Pathology. Deidre MacKenna has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Phenex Inc. Deidre MacKenna has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Blade Therapeutics. Deidre MacKenna has received stock or an ownership interest from Autobahn Therapeutics. Deidre MacKenna has received stock or an ownership interest from Blade Therapeutics.