Leriglitazone: frustration and hope in adrenoleukodystrophy

X-linked adrenoleukodystrophy is a rare disease caused by loss of function mutations in the ABCD1 gene. The clinical spectrum in males ranges from adrenocortical insufficiency (Addison's disease) to myeloneuropathy, with prominent spastic gait and bladder disturbance, and to cerebral leukodystrophy, often resulting in rapidly progressive dementia and disability. 1 Engelen M Kemp S de Visser M et al. X-linked adrenoleukodystrophy (X-ALD): clinical presentation and guidelines for diagnosis, follow-up and management. Orphanet J Rare Dis. 2012; 7: 51 Crossref PubMed Scopus (335) Google Scholar ABCD1 encodes the peroxisomal membrane adrenoleukodystrophy protein, which is involved in the transmembrane transport and beta-oxidation of very long-chain fatty acids (VLCFAs). A defect in adrenoleukodystrophy protein results in elevated concentrations of VLCFA in plasma and accumulation of VLCFA-CoA esters in various tissues, including the adrenal glands and the white matter of the brain and spinal cord. 2 Moser HW Moser AB Frayer KK et al. Adrenoleukodystrophy: increased plasma content of saturated very long chain fatty acids. Neurology. 1981; 31: 1241-1249 Crossref PubMed Google Scholar VLCFAs are extremely hydrophobic and their accumulation disrupts cell membranes and induces oxidative stress and microglia activation. 3 Whitcomb RW Linehan WM Knazek RA Effects of long-chain, saturated fatty acids on membrane microviscosity and adrenocorticotropin responsiveness of human adrenocortical cells in vitro. J Clin Invest. 1988; 81: 185-188 Crossref PubMed Scopus (141) Google Scholar , 4 Eichler FS Ren JQ Cossoy M et al. Is microglial apoptosis an early pathogenic change in cerebral X-linked adrenoleukodystrophy?. Ann Neurol. 2008; 63: 729-742 Crossref PubMed Scopus (122) Google Scholar Safety and efficacy of leriglitazone for preventing disease progression in men with adrenomyeloneuropathy (ADVANCE): a randomised, double-blind, multi-centre, placebo-controlled phase 2–3 trialThe primary endpoint was not met, but leriglitazone was generally well tolerated and rates of adverse events were in line with the expected safety profile for this drug class. The finding that cerebral adrenoleukodystrophy, a life-threatening event for patients with adrenomyeloneuropathy, occurred only in patients in the placebo group supports further investigation of whether leriglitazone might slow the progression of cerebral adrenoleukodystrophy. Full-Text PDF