Inhibition Of Lipoprotein Secretion

TECH FIELD(S)
Drug Discovery - Gene therapy

FEATURES
Elevated levels of low-density lipoproteins (LDLs) are strongly correlated with severe forms of hypercholesterolemia. Because patients vary in responsiveness to “statins” – drugs that inhibit the activity of a particular enzyme in cholesterol biosynthesis –new treatments for high cholesterol are needed. This invention provides a novel means to reduce LDL levels in the bloodstream. Described is a gene construct composed of a promoter expressing a fusion protein. The fusion protein contains a truncated low density lipoprotein receptor (LDLR) linked to a localization domain (KDEL). The KDEL directs the fusion protein to the cell interior of cells where it is sequestered in the endoplasmic reticulum. Inside cells, the LDLR binds to apoB, the precursor of a protein that forms LDL. The LDLR regulates apoB by degrading it and inhibiting its secretion into the bloodstream, thus lowering LDL levels. This genetic construct of LDLR plus KDEL can be transfected into cells or delivered directly to individuals in vivo in order to reduce the levels of apoB and thus, LDL.

BENEFITS

• These genetic constructs can be effectively introduced into any mammal to decrease levels of LDL
• The mechanism operates at cellular levels that are similar in all mammals
• KDEL is fused to LDLR in such a manner as to maintain the apoB binding properties of LDLR while permitting LDLR’s localization inside the cell
• A variety of localization domains can be used, as well as proteins with impaired glycosylation that can interact with chaparone proteins to inhibit protein secretion
• By producing a defective LDLR that is trapped in cells, there is no exposure to the immune system, thereby avoiding any potential autoimmune response
• This methodology can also be used to decrease plasma tricglyceride levels in patients with hypercholesterolemia

INVENTOR(S)
Alan D. Attie, Donald L. Gillian-Daniel, Paul W. Bates

INTELLECTUAL PROPERTY STATUS
View U.S. Patent No. 7,517,860 in PDF format

CONTACT INFORMATION
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