Overexpression of ABCD2, the closest homologue of ABCD1, has been shown to normalize the biochemical defect both in human X-ALD fibroblasts (2) and in Abcd1-deficient mice (3). However, at the intrinsic level of expression in X-ALD patients, ABCD2 apparently does not compensate for ABCD1-deficiency. This is likely due to their complementary expression patterns and insufficient levels of ABCD2 in disease-relevant cell types. Thus, induction of endogenous ABCD2 transcription represents a potential novel therapeutic target for X-ALD. To this end, we have characterized the human and murine ABCD2 promoters and gained substantial insight into the complex regulation of ABCD2 gene expression. We are now screening for drugs that are able to induce ABCD2 expression in specific cell types. Because HSCT can stop inflammation in cerebral ALD (and possibly also the AMN symptoms) and of the grafted cells, mainly macrophages/monocytes persist in the CNS after HSCT, we consider microglia/macrophages a major target for therapeutic ABCD2 overexpression. Since ubiquitous, transgenic overexpression of ABCD2 can prevent both the accumulation of VLCFA and the appearance of AMN-like symptoms in murine X-ALD (3), we will construct a mouse model, in which transgenic ABCD2 expression is driven by the microglia/macrophage-specific Iba1 promoter.
The principle of pharmacological induction of redundant genes as a therapeutic approach. ALDR is with 66 %identity the protein most closely related to ALDP, which is the disease associated protein in X-ALD. Tissues associated with the disease, such as brain white matter, adrenal cortex and testis show high levels of ALDP but relatively low abundance of ALDR. The new approach attempts to induced ABCD2 gene expression pharmacologically in macrophages/microglia to increase the level of ALDR to compensate for functional loss of ALDP.
To read more about the principle of the approach -pdf-
To learn about the regulation of the ABCD2 promoter -pdf-
To learn about cholesterol regulation of the ABCD2 promoter -pdf-
