Small molecule helps fix ‘Lorenzo’s Oil’ gene mutation

Researchers have identified a small organic molecule that may help fix the genetic defect that causes X-linked adrenoleukodystrophy (X-ALD), the rare disease featured in the 1992 movie “Lorenzo’s Oil.”

X-ALD, which affects 1 in 20,000 to 50,000 people worldwide, typically kills boys diagnosed in early childhood, and an adult form impairs nervous system function progressively. The underlying problem is an inherited mutation in the gene for ABCD1, a protein that transports very-long-chain fatty acids (VLCFAs) to units inside cells called peroxisomes, which break them down. The mutation allows VLCFAs to overaccumulate in the brain and spinal cord, where they destroy myelin sheaths on brain and spinal cord nerve cells by an unknown mechanism.

Director of chemical biology Thomas S. Scanlan and coworkers at Oregon Health & Science University show that sobetirome, a small molecule they discovered earlier, reduces VLCFA levels in the brains of X-ALD mice (Endocrinology 2017, DOI: 10.1210/en.2016-1842). The compound works by activating the gene that makes ABCD2, a close relative of ABCD1 that does not contain an inherited mutation, partially restoring normal VLCFA breakdown.

As depicted in the movie, the parents of Lorenzo Odone, who was six when diagnosed with X-ALD, discovered Lorenzo’s Oil, an extract of rapeseed and olive oils that inhibits VLCFA synthesis. The product is available commercially but is still experimental. Lorenzo lived much longer than expected but died at age 30.

Several drug candidates have tried to boost expression of the gene for ABCD2, but none has been successful. Scanlan and coworkers hope sobetirome, an orally administered compound that activates the thyroid hormone receptor and can reach the brain, might do better. After oral dosing for 12 weeks, it lowered brain VLCFAs 15 to 20% in X-ALD mice. Is that sufficient to be therapeutic? Only clinical trials will tell.

Sobetirome caused few side effects in an earlier human clinical trial for cholesterol lowering. NeuroVia, in Cambridge, Mass., which Scanlan helped found, is developing sobetirome clinically to treat X-ALD, and the Food & Drug Administration has given the compound orphan-drug status, which provides development incentives such as tax credits.

Stephane Savary of the University of Bourgogne, who cloned the gene for ABCD2 and studied the in vitro effects of sobetirome on expression of the gene, comments that the study’s “results in mice are really encouraging and deserve a clinical trial.”