Farneslytransferase 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: Patent

Abstract

Although it can be farnesylated, the mutant lamin A protein expressed in Hutchison 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 number7838531
IPCA61K 49/00 (20060101); A61K 31/445 (20060101); A01N 43/42 (20060101); C12Q 1/48 (20060101
StatePublished - 1800

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

Keywords

    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. A61K 49/00 (20060101); A61K 31/445 (20060101); A01N 43/42 (20060101); C12Q 1/48 (20060101. Farneslytransferase Inhibitors for Treatment of Laminopathies, Cellular Aging and Atherosclerosis (Patent No. 7838531.)

    Farneslytransferase 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.: A61K 49/00 (20060101); A61K 31/445 (20060101); A01N 43/42 (20060101); C12Q 1/48 (20060101. Patent No.: 7838531.

    Research output: Patent

    Gordon, LB, Collins, FS, Glover, T, Glynn, MW, Capell, BC, Cox, AD & Der, CJ 1800, Farneslytransferase Inhibitors for Treatment of Laminopathies, Cellular Aging and Atherosclerosis, Patent No. 7838531, IPC No. A61K 49/00 (20060101); A61K 31/445 (20060101); A01N 43/42 (20060101); C12Q 1/48 (20060101.
    Gordon LB, Collins FS, Glover T, Glynn MW, Capell BC, Cox AD et al, inventors. Farneslytransferase Inhibitors for Treatment of Laminopathies, Cellular Aging and Atherosclerosis. A61K 49/00 (20060101); A61K 31/445 (20060101); A01N 43/42 (20060101); C12Q 1/48 (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). / Farneslytransferase Inhibitors for Treatment of Laminopathies, Cellular Aging and Atherosclerosis. IPC No.: A61K 49/00 (20060101); A61K 31/445 (20060101); A01N 43/42 (20060101); C12Q 1/48 (20060101. Patent No.: 7838531.
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    AU - Collins,Francis S.

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    AU - Capell,Brian C.

    AU - Cox,Adrienne D.

    AU - Der,Channing J.

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    N2 - Although it can be farnesylated, the mutant lamin A protein expressed in Hutchison 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 Hutchison 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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