Induced pluripotent stem cell models from X-linked adrenoleukodystrophy patients.

Objective: Because of a lack of an appropriate animal model system and the inaccessibility of human oligodendrocytes in vivo, X-linked adrenoleukodystrophy (X-ALD)-induced pluripotent stem cells (iPSCs) would provide a unique cellular model for studying etiopathophysiology and development of therapeutics for X-ALD.

Methods: We generated and characterized iPSCs of the 2 major types of X-ALD, childhood cerebral ALD (CCALD) and adrenomyeloneuropathy (AMN), and differentiated them into oligodendrocytes and neurons. We evaluated disease-relevant phenotypes by pharmacological and genetic approaches.

Results: We established iPSCs from the patients with CCALD and AMN. Both CCALD and AMN iPSCs normally differentiated into oligodendrocytes, the cell type primarily affected in the X-ALD brain, indicating no developmental defect due to the ABCD1 mutations. Although low in X-ALD iPSCs, very long chain fatty acid (VLCFA) level was significantly increased after oligodendrocyte differentiation. VLCFA accumulation was much higher in CCALD oligodendrocytes than AMN oligodendrocytes but was not significantly different between CCALD and AMN neurons, indicating that the severe clinical manifestations in CCALD might be associated with abnormal VLCFA accumulation in oligodendrocytes. Furthermore, the abnormal accumulation of VLCFA in the X-ALD oligodendrocytes can be reduced by the upregulated ABCD2 gene expression after treatment with lovastatin or 4-phenylbutyrate.

Interpretation: X-ALD iPSC model recapitulates the key events of disease development (ie, VLCFA accumulation in oligodendrocytes), provides new clues for better understanding of the disease, and allows for early and accurate diagnosis of the disease subtypes. X-ALD oligodendrocytes can be a useful cell model system to develop new therapeutics for treating X-ALD.