Therapeutic strategies for x-linked adrenoleukodystrophy, a representative peroxisomal disorder

X-linked adrenoleukodystrophy (X-ALD) is the most frequent peroxisomal disorder, and is caused by dysfunction of the peroxisomal ABC protein ABCD1. X-ALD patients with the most severe phenotype display cerebral inflammatory demyelination. In X-ALD, VLCFA accumulation, a characteristic feature of all patients, is thought to be the main culprit underlying the pathogenesis. However, the mechanisms by which the VLCFA accumulated in the brain causes demyelinating neurodegeneration have not yet been elucidated. At present, hematopoietic stem cell transplantation (HSCT) at an early symptomatic state is effective in halting disease progression, thus allowing long-term survival. Therefore, early diagnosis and conduct timely transplantation are particularly important to improve the outcome of HSCT. However, HSCT is always associated with significant mortality risk and the difficulty of finding a matching donor. Recently, genetically modified hematopoietic stem cells for ex vivo gene therapy have been tested as an alternative option and are expected to eventually become standard treatment for X-ALD. In parallel, the development of therapeutic drugs that can attenuate the symptoms or maintain the asymptomatic stage for patients diagnosed with X-ALD is in progress. To date, many candidate compounds have been reported. In this chapter, we focus on the current state of HSCT and pharmacological treatments, and describe the necessity for newborn screening and the identification of predictive biological markers in X-ALD.