Expert Opinion on Orphan Drugs. 3:1447-1459. 2015.
Pathophysiology and emerging therapeutic strategies in Pelizaeus–Merzbacher disease
INTRODUCTION: Pelizaeus–Merzbacher disease (PMD) is an X-linked recessive disorder caused by mutations in the proteolipid protein 1 (PLP1) gene, which encodes PLP1 and DM20. PMD is characterized by a defect in myelin formation associated with PLP1 gene mutations (i.e., exonic and intronic mutations, duplication, or deletion of the entire gene). A combination of magnetic resonance imaging (MRI) and genetic testing is essential to diagnose PMD. The disease phenotype manifests due to the loss of PLP/DM20 function or the toxicity of mutant PLP/DM20 or overexpressed PLP/DM20.
AREAS COVERED: Potential approaches at the RNA level include restoring correct splicing with oligonucleotides and decreasing PLP1 expression using a transcriptional activator antagonist. Two approaches used in mouse models that have clinical potential include cholesterol supplementation and use of compounds that decrease the excessive unfolded protein response (UPR) in the endoplasmic reticulum (ER). Two types of cell-based therapy, bone marrow transplantation and stem cell engraftment, were recently employed safely in humans.
EXPERT OPINION: Elucidation of PMD pathophysiology has enabled several recent therapeutic approaches. Administration of cholesterol or curcumin in mouse models of PMD reportedly extends survival time. Stem cell therapies await evaluation of long-term effectiveness and safety in patients with PMD.