Management of adrenoleukodystrophy: From pre-clinical studies to the development of new therapies.

ABSTRACT

X-linked adrenoleukodystrophy (X-ALD) is an inherited neurodegenerative disorder associated with mutations of the ABCD1 gene that encodes a peroxisomal transmembrane protein. It results in accumulation of very long chain fatty acids in tissues and body fluid. Along with other factors such as epigenetic and environmental involvement, ABCD1 mutation-provoked disorders can present different phenotypes including cerebral adrenoleukodystrophy (cALD), adrenomyeloneuropathy (AMN), and peripheral neuropathy. cALD is the most severe form that causes death in young childhood. Bone marrow transplantation and hematopoietic stem cell gene therapy are only effective when performed at an early stage of onsets in cALD. Nonetheless, current research and development of novel therapies are hampered by a lack of in-depth understanding disease pathophysiology and a lack of reliable cALD models. The Abcd1 and Abcd1/Abcd2 knock-out mouse models as well as the deficiency of Abcd1 rabbit models created in our lab, do not develop cALD phenotypes observed in human beings. In this review, we summarize the clinical and biochemical features of X-ALD, the progress of pre-clinical and clinical studies. Challenges and perspectives for future X-ALD studies are also discussed.