Adrienne Leigh Cox, 471086 Abbey Ln, Collegeville, PA 19426

2015001, Jan 15, 2015

Jul 21, 2014

14/336457

- Rockville MD, US
- Peabody MA, US
- Ann Arbor MI, US
- Chapel Hill NC, US
Brian C. CAPELL - Philadelphia PA, US
Adrienne D. COX - Chapel Hill NC, US
Channing J. DER - Chapel Hill NC, US

A61K 31/4545
A61K 31/4709

514290, 514303, 514312

Although it can be farnesylated, the mutant lamin A protein expressed in Hutchinson Gilford Progeria Syndrome (HGPS) cannot be defarnesylated because the characteristic mutation causes deletion of a cleavage site necessary for binding the protease ZMPSTE24 and effecting defarnesylation. The result is an aberrant farnesylated protein (called “progerin”) that alters normal lamin A function as a dominant negative, as well as assuming its own aberrant function through its association with the nuclear membrane. The retention of farnesylation, and potentially other abnormal properties of progerin and other abnormal lamin gene protein products, produces disease. Farnesyltransferase inhibitors (FTIs) (both direct effectors and indirect inhibitors) will inhibit the formation of progerin, cause a decrease in lamin A protein, and/or an increase prelamin A protein. Decreasing the amount of aberrant protein improves cellular effects caused by and progerin expression. Similarly, treatment with FTIs should improve disease status in progeria and other laminopathies. In addition, elements of atherosclerosis and aging in non-laminopathy individuals will improve after treatment with farnesyltransferase inhibitors.