Pharmacological treatment based on gene redundancy: A novel therapeutic approach for X-linked adrenoleukodystrophy

X-linked adrenoleukodystrophy (X-ALD; OMIM 300100), the most frequent peroxisomal disorder, presents as a severe neurodegenerative disease with widely varying clinical phenotypes. The biochemical characteristic of X-ALD is the accumulation of very long-chain fatty acids (VLCFA), which should normally be degraded by the peroxisomal b-oxidation pathway, in plasma and tissues of X-ALD patients. It is still a mystery how increased VLCFA levels are connected to the pathophysiology of X-ALD, i.e. the loss of myelin on nerve fibers and the destruction of adrenocortical cells. In 1993, the disease-associated gene ABCD1 (ALD) was identified by Mosser and coworkers using a positional cloning strategy [1] and surprisingly turned out to encode a peroxisomal ATP-binding cassette (ABC) half transporter, the adrenoleukodystrophy protein (ALDP). Now, eleven years later, the function of this protein still remains to be elucidated and no satisfying cure for the fatal course of X-ALD is available. Next to ALDP, three additional mammalian peroxisomal ABC half transporters have been identified: ALDRP, PMP70 and P70R, which share 66, 35 and 25 % identity, respectively, with ALDP and are encoded by the genes ABCD2, ABCD3 and ABCD4, respectively. Thus, ALDR is the protein most closely related to ALDP and based on the high degree of amino acid conservation, hope was raised that ALDP and ALDR would have similar or overlapping functions. Already at that time, a novel strategy for treatment of X-ALD was suggested based on pharmacological stimulation of the related ABCD2 gene in disease-relevant cell types, in order to increase the amount of ALDRP to compensate for loss of ALDP in X-ALD patients. The principle of this therapeutic approach and the results obtained so far will be the subject of this chapter.