Progesterone antagonist therapy in a Pelizaeus-Merzbacher mouse model

Am J Hum Genet. 2014 Apr 3;94(4):533-46. doi: 10.1016/j.ajhg.2014.03.001. Epub 2014 Mar 27.


Pelizaeus-Merzbacher disease (PMD) is a severe hypomyelinating disease, characterized by ataxia, intellectual disability, epilepsy, and premature death. In the majority of cases, PMD is caused by duplication of PLP1 that is expressed in myelinating oligodendrocytes. Despite detailed knowledge of PLP1, there is presently no curative therapy for PMD. We used a Plp1 transgenic PMD mouse model to test the therapeutic effect of Lonaprisan, an antagonist of the nuclear progesterone receptor, in lowering Plp1 mRNA overexpression. We applied placebo-controlled Lonaprisan therapy to PMD mice for 10 weeks and performed the grid slip analysis to assess the clinical phenotype. Additionally, mRNA expression and protein accumulation as well as histological analysis of the central nervous system were performed. Although Plp1 mRNA levels are increased 1.8-fold in PMD mice compared to wild-type controls, daily Lonaprisan treatment reduced overexpression at the RNA level to about 1.5-fold, which was sufficient to significantly improve the poor motor phenotype. Electron microscopy confirmed a 25% increase in the number of myelinated axons in the corticospinal tract when compared to untreated PMD mice. Microarray analysis revealed the upregulation of proapoptotic genes in PMD mice that could be partially rescued by Lonaprisan treatment, which also reduced microgliosis, astrogliosis, and lymphocyte infiltration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal
  • Estrenes / pharmacokinetics
  • Estrenes / pharmacology
  • Estrenes / therapeutic use*
  • Gene Expression Regulation / drug effects
  • Hormone Antagonists / pharmacokinetics
  • Hormone Antagonists / pharmacology
  • Hormone Antagonists / therapeutic use*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Myelin Proteolipid Protein / genetics
  • Pelizaeus-Merzbacher Disease / drug therapy*
  • Phenotype
  • Progesterone / antagonists & inhibitors*
  • RNA, Messenger / genetics


  • Estrenes
  • Hormone Antagonists
  • Myelin Proteolipid Protein
  • Plp1 protein, mouse
  • RNA, Messenger
  • Progesterone
  • lonaprisan

Associated data

  • GEO/GSE55315