laminopathy Treatment with Farnesyltransferase Inhibitor

University Of California Los Angeles, Los Angeles CA

Investigators

Linked publications & trials

Abstract

[unreadable] DESCRIPTION (provided by applicant): Mutations in LMNA (the gene for lamin A and lamin C) are associated with a host of different human diseases, known as laminopathies. Prelamin A, the precursor to lamin A, undergoes a series of posttranslational modifications, including farnesylation, endoproteolytic cleavage, and carboxylmethylation. In Hutchinson-Gilford progeria syndrome, prelamin A processing is abnormal, leading to an accumulation of farnesylated prelamin A. This farnesyl-prelamin A causes misshapen nuclei in cells and aging-like disease phenotypes. Studies in cultured cells have shown that blocking farnesylation with an FTI reduces the frequency of misshapen nuclei. To extend those studies, I would like to test the possibility that FTIs might "cure" disease phenotypes in mouse models of progeria. One concern is that the accumulation of nonfarnesylated prelamin A (in the setting of FTI treatment) might prove to be toxic. To assess that possibility, I will create and characterize a gene-targeted mouse that expresses a nonfarnesylated version of prelamin A. Finally, I will test the possibility that FTIs might delay or prevent disease phenotypes in gene- targeted mice harboring a missense mutation (H222P) causing Emery-Dreifuss muscular dystrophy. [unreadable] [unreadable] [unreadable]