Thyroid drug corrects metabolic defect in a rare genetic disorder

Tom Scanlan, Ph.D., and Meredith D. Hartley, Ph.D.

In 2017, research led by Tom Scanlan, Ph.D., professor of chemical physiology and biochemistry, OHSU School of Medicine, found that sobetirome, a synthetic thyroid drug developed in his lab years ago to lower cholesterol, corrected the biochemical abnormality in the devastating, rare neurodegenerative disease adrenoleukodystrophy or ALD.

The findings, in a mouse model, laid the groundwork for clinical trials in humans.

Image above: Tom Scanlan, Ph.D. (left) and Meredith D. Hartley, Ph.D. look over data on March, 10, 2017, during their earlier research on the synthetic thyroid hormone. (OHSU/Kristyna Wentz-Graff)

Now, a new study by the Scanlan lab demonstrated that Sob-AM2 delivers a more potent and effective therapy for the most common type of ALD – adrenomyeloneuropathy (AMN) – than the original drug sobetirome.

Sob-AM2 is a chemical compound created from sobetirome using a prodrug strategy that specifically targets the central nervous system (CNS). Development of Sob-AM2 involved a collaboration of scientists and physicians with expertise ranging across chemistry, neurology, genetics, advanced imaging, physiology and pharmacology.

Sob-AM2, Scanlan’s team found, potently corrects the disorder’s metabolic defect particularly in the spinal cord in mice with the same genetic defect as ALD patients, opening a path to effective drug therapies for people living with AMN.

“The future for this project is clinical trials in X-ALD patients and translating our basic science into the clinic,” said Scanlan.

The paper “Pharmacological Complementation Remedies an Inborn Error of Lipid Metabolism” published in the journal Cell Chemical Biology is the School of Medicine’s Paper of the Month.

“It’s a clever and multidisciplinary approach to a translational challenge,” said Mary Heinricher, Ph.D., associate dean of research, OHSU School of Medicine.

Transportation breakdown

People with ALD have an inborn error of metabolism that interferes with their CNS, causing demyelination and destruction of the nerves’ ability to relay information. Symptoms may include balance and walking difficulties, weakness and stiffness in the legs, incontinence, speech difficulties, behavioral abnormalities, vision loss or seizures, and even death in the form of the disease that affects the brain called cerebral ALD.

In previous research, scientists have established that people with ALD have mutations in a gene called ABCD1, said Scanlan. These mutations cause a breakdown in an important molecular process.

Here’s how it works. Normally, the ABCD1 gene produces a key protein called adrenoleukodystrophy protein (ALDP). The job of ALDP is to transport a class of lipid molecules – very long-chain fatty acids (VLCFAs) – into small cellular sacs called peroxisomes where the fatty acid molecules are degraded by oxidation.

But ABCD1 mutations disable the biochemical function of ALDP. Without enough ALDP to move them into peroxisomes, VLCFAs build up, causing high levels in cells throughout the body.

Studies suggest that these high levels are likely toxic to myelin – the sheaths of fatty tissue that insulate nerves in the brain and spinal cord and facilitate information flow throughout the nervous system. Researchers are working to understand why the VLCFA toxicity triggers myelin breakdown (demyelination) in the CNS.

The Scanlan lab, for its part, saw an opportunity to help people with ALD by developing a drug therapy that reduces VLCFA build-up, which should ease neurological symptoms and halt progression of the disease.

Significant and sustained VLCFA reductions

Their approach? ABCD2.

ABCD2 is a gene similar to ABCD1 that can compensate for ABCD1 defects and restore VLCFA oxidation in peroxisomes.

“Sobetirome and Sob-AM2 work because they activate or upregulate ABCD2, a gene which is classically thyroid hormone-regulated,” said Scanlan.

In their dose-response study, the team treated ABCD1-deficient mice with Sob-AM2, which activated ABCD2 to correct the ABCD1 defects. They measured the levels of VLCFAs in the brain and spinal cord, as well as blood and organs.

“We found that Sob-AM2 was more potent than sobetirome at reducing elevated VLCFA in the CNS, particularly in the spinal cord which is relevant for AMN,” said Scanlan. “Sob-AM2 also reduced elevated VLCFA in blood and peripheral tissue, but not as potently as sobetirome, which makes sense because Sob-AM2 targets the CNS and sobetirome targets the periphery.”

The findings established that Sob-AM2 provides significant and sustained reductions to the elevated levels of VLCFA that are responsible for the pathology in ALD.  The next step is clinical trials in patients.

Citation

Hartley et al., Pharmacological Complementation Remedies an Inborn Error of Lipid Metabolism, Cell Chemical Biology (2020), https://doi.org/10.1016/j.chembiol.2020.02.008

Author List

Meredith D. Hartley, Mitra D. Shokat, Margaret J. DeBell, Tania Banerji, Lisa L. Kirkemo, and Thomas S. Scanlan

This research was supported by the National Institutes of Health grant DK52798 and the Oregon Health & Sciences University (OHSU) Laura Fund for Innovation in Multiple Sclerosis. In the interest of ensuring the integrity of our research and as part of our commitment to public transparency, OHSU actively regulates, tracks and manages relationships that our researchers may hold with entities outside of OHSU. In regards to this research, Scanlan and Hartley have significant interests in Autobahn Therapeutics, a company that may have a commercial interest in the results of this research. Review details of OHSU’s conflict of interest program to find out more about how we manage these business relationships.

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