Current and future pharmacological treatment strategies in X-linked adrenoleukodystrophy.
Mutations in the ABCD1 gene cause the clinical spectrum of the neurometabolic disorder X-linked adrenoleukodystrophy/adrenomyeloneuropathy (X-ALD/AMN). Currently, the most efficient therapeutic opportunity for patients with the cerebral form of X-ALD is hematopoietic stem cell transplantation and possibly gene therapy of autologous hematopoietic stem cells. Both treatments, however, are only accessible to a subset of X-ALD patients, mainly because of the lack of markers that can predict the onset of cerebral demyelination. Moreover, for female or male X-ALD patients with AMN, currently only unsatisfying therapeutic opportunities are available. Thus, this review focuses on current and urgently needed future pharmacological therapies. The treatment of adrenal and gonadal insufficiency is well established, whereas applications of immunomodulatory and immunosuppressive drugs have failed to prevent progression of cerebral neuroinflammation. The use of Lorenzo's oil and the inefficacy of lovastatin to normalize very-long-chain fatty acids in clinical trials as well as currently experimental and therefore possible future therapeutic strategies are reviewed. The latter include pharmacological gene therapy mediated by targeted upregulation of ABCD2, the closest homolog of ABCD1, antioxidative drug treatment, small molecule histone deacetylase inhibitors such as butyrates and valproic acid, and other neuroprotective attempts.
Berger
Johannes
J
Center for Brain Research, Medical University of Vienna, Vienna, Austria. johannes.berger@meduniwien.ac.at
Pujol
Aurora
A
Aubourg
Patrick
P
Forss-Petter
Sonja
S
D000326:Adrenoleukodystrophy / Q000378:metabolism / Q000628:therapy*; D004338:Drug Combinations; D004883:Erucic Acids; D005227:Fatty Acids / Q000378:metabolism; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D014304:Triolein
D004338:Drug Combinations; D004883:Erucic Acids; D005227:Fatty Acids; C079420:Lorenzo's oil; D014304:Triolein