Farnesyltransferase Inhibitors for Treatment of Laminopathies, Cellular Aging and Atherosclerosis

Leslie B. Gordon (Inventor), Francis S. Collins (Inventor), Thomas Glover (Inventor), Michael W. Glynn (Inventor), Brian C. Capell (Inventor), Adrienne D. Cox (Inventor), Channing J. Der (Inventor)

Research output: ResearchPatent

Abstract

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.
LanguageEnglish
Patent number8257915
IPCC12Q 1/00 (20060101); C12Q 1/02 (20060101)
StatePublished - 1800

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Farnesyltranstransferase
Cell Aging
Atherosclerosis
Proteins
Lamin Type A
Progeria
Lamins
Prenylation
Sequence Deletion
Nuclear Envelope
Peptide Hydrolases
Binding Sites
prelamin A

Cite this

Gordon, L. B., Collins, F. S., Glover, T., Glynn, M. W., Capell, B. C., Cox, A. D., & Der, C. J. (1800). IPC No. C12Q 1/00 (20060101); C12Q 1/02 (20060101). Farnesyltransferase Inhibitors for Treatment of Laminopathies, Cellular Aging and Atherosclerosis (Patent No. 8257915.)

Farnesyltransferase Inhibitors for Treatment of Laminopathies, Cellular Aging and Atherosclerosis. / Gordon, Leslie B. (Inventor); Collins, Francis S. (Inventor); Glover, Thomas (Inventor); Glynn, Michael W. (Inventor); Capell, Brian C. (Inventor); Cox, Adrienne D. (Inventor); Der, Channing J. (Inventor).

IPC No.: C12Q 1/00 (20060101); C12Q 1/02 (20060101). Patent No.: 8257915.

Research output: ResearchPatent

Gordon, LB, Collins, FS, Glover, T, Glynn, MW, Capell, BC, Cox, AD & Der, CJ 1800, Farnesyltransferase Inhibitors for Treatment of Laminopathies, Cellular Aging and Atherosclerosis, Patent No. 8257915, IPC No. C12Q 1/00 (20060101); C12Q 1/02 (20060101).
Gordon LB, Collins FS, Glover T, Glynn MW, Capell BC, Cox AD et al, inventors. Farnesyltransferase Inhibitors for Treatment of Laminopathies, Cellular Aging and Atherosclerosis. C12Q 1/00 (20060101); C12Q 1/02 (20060101). 1800
Gordon, Leslie B. (Inventor) ; Collins, Francis S. (Inventor) ; Glover, Thomas (Inventor) ; Glynn, Michael W. (Inventor) ; Capell, Brian C. (Inventor) ; Cox, Adrienne D. (Inventor) ; Der, Channing J. (Inventor). / Farnesyltransferase Inhibitors for Treatment of Laminopathies, Cellular Aging and Atherosclerosis. IPC No.: C12Q 1/00 (20060101); C12Q 1/02 (20060101). Patent No.: 8257915.
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abstract = "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.",
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AU - Capell,Brian C.

AU - Cox,Adrienne D.

AU - Der,Channing J.

N1 - Status: published applicationnumber: 12/905,838 usclass: 435/4 ; 435/29 applicationnumber: 12/905,838

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N2 - 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.

AB - 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.

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