Our objectives are to understand the function of prelamin A and lamin C (alternatively spliced products of the LMNA gene) in health and disease, and to develop new strategies to treat prelamin A diseases, which include progeroid syndromes. In this application, we will explore a new therapeutic strategy for prelamin A diseases that was suggested by a new discovery in lamin A biology in the central nervous system. The classic progeroid syndrome of children, Hutchinson-Gilford progeria syndrome (HGPS), is caused by a mutant form of prelamin A. Affected children are healthy at birth but soon develop several disease phenotypes that resemble premature aging. For the past 9 years, we have worked to investigate the biology of nuclear lamins with an eye towards finding mechanism-based therapies for diseases of the nuclear lamina (laminopathies). This approach led us to propose, in 2004, that protein farnesylation might be important for the pathogenesis of prelamin A-related progeroid syndromes. Since then, we have tested inhibitors of protein farnesyltransferase (FTIs) in mouse models of progeria, which prompted an FTI clinical trial in children with HGPS. That trial has been completed, and it appeared that the FTI improved several disease phenotypes. However, it is very clear that FTI treatment falls far short of a cure, both in mouse models and in humans. Fresh therapeutic strategies are needed. We recently uncovered a novel feature of lamin A biology that suggested a pathway to a new treatment strategy for prelamin A diseases. We discovered that neurons express lamin C but very little prelamin A. This observation likely explains why children with HGPS are spared from neurodegenerative disease. More importantly, our observation led us to think seriously about new therapeutic strategies for progeria. Prelamin A synthesis is negligible in the brain, and the brain is spared from disease in HGPS. If we can identify strategies for reducing prelamin A levels in peripheral tissues (mirroring the situation in the brain), it might be possible to prevent-or even reverse-the disease phenotypes of HGPS and other prelamin A diseases. For the next 5 years, we will investigate mechanisms by which the brain regulates prelamin A synthesis. In addition, we will investigate the DNA sequences and proteins that regulate lamin C and prelamin A synthesis. We will also work to characterize antisense oligonucleotides that alter splicing and tip the balance towards lamin C production at the expense of prelamin A. Finally, we will determine if reducing prelamin A synthesis in peripheral tissues ameliorates disease phenotypes in a new mouse model of HGPS.

Public Health Relevance

Genetic defects that lead to an accumulation of mutant forms of prelamin A lead to premature aging disorders such as Hutchinson-Gilford progeria syndrome (HGPS). We recently discovered a new molecular mechanism that suppresses the production of prelamin A in the brain. Building on that discovery, we have pioneered a new treatment strategy for HGPS and other prelamin A-related progeroid disorders.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
1R01AG047192-01
Application #
8670322
Study Section
Therapeutic Approaches to Genetic Diseases (TAG)
Program Officer
Guo, Max
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Los Angeles
State
CA
Country
United States
Zip Code
90095