University of Pennsylvania

Aventis Pharmaceuticals Inc.

Daniel J Rader

James M Wilson

Anna P Tretiakova

Michael C Jaye

Dilip V Amin

Victoria J South

Kevin J Lynch

Kim-Anh Thi Doan

John A Krawiec

Dawn Marchadier

Cyrille Maugeais

Suryanrayan Somanathan

Devin Christopher

A synthetic or recombinant human lecithin cholesterol acyltransferase (LCAT) variant is provided which comprises an LCAT enzyme having a substitution at position 114 based on the residue numbering of wild-type (WT) human LCAT [SEQ ID NO:1], wherein said variant is characterized by one or more of: (i) an esterification rate higher than the esterification rate of WT human LCAT; and/or (ii) an association with higher density lipoprotein levels as compared to subjects having WT LCAT. Also provided are vectors encoding the variant, compositions containing same, and methods of using the variant proteins and vectors for treatment of a variety of disorders associated with defective wt LCAT.

Compositions comprising a lecithin cholesterol acyltransferase variant and uses thereof

Regimens useful in reducing the frequency of apheresis in a human patient having familial hypercholesterolemia are described. The method involves administering to the human subject via a peripheral vein by infusion of a suspension of replication deficient recombinant adeno-associated virus (rAAV).

Gene therapy for treating familial hypercholesterolemia

A recombinant vector having an expression cassette is provided which comprises a modified human low density lipoprotein receptor (hLDLR) gene is provided, wherein said hLDLR gene encodes a modified hLDLR comprising (a) one or more of the following amino acid substitutions: L318H, N295D, H306D, V307D, N309A, D310N, L318H, and/or L318D; or (b) an amino acid substitution of any of (a) in combination with one or more of the following amino acid substitutions: K796, K809R and/or C818A. Also provided are pharmaceutical compositions containing this vector and uses therefor in lowering cholesterol and/or treating familial hypercholesterolemia.

LDLR variants and their use in compositions for reducing cholesterol levels

The present invention provides methods and compositions for treating hyperlipidemia and/or hypercholesterolemia comprising administering to the subject an effective amount of an MTP inhibitor to inhibit hyperlipidemia and/or hypercholesterolemia in said subject, wherein said administration comprises an escalating series of doses of the MTP inhibitor. In some embodiments the method comprises administering at least three step-wise, increasing dosages of the MTP inhibitor to the subject. In some embodiments, the method further comprises the administration of one or more other lipid modifying compounds.

Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side-effects

Compositions and regimens useful in reducing one or more of: LDL-cholesterol, total cholesterol, and/or fasting triglycerides in a subject, and/or modifying fractional catabolic rate (FCR) of LDL apolipoprotein B (apoB) from baseline to a selected time point after rAAV administration are provided. The method involves administering to the human subject via a peripheral vein by infusion of a suspension of replication deficient recombinant adeno-associated virus (rAAV).

Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side effects

The present invention relates to compositions for use in raising or lowering the level of LIPG polypeptide in a patient. Embodiments of the composition include compositions comprising: an anti-sense nucleic acid; a neutralizing antibody; an intracellular binding protein; an inhibitor which inhibits the enzymatic activity of LIPG polypeptide; an inhibitor which inhibits the expression of LIPG gene; a ribozyme; an LIPG polypeptide; an enhancer which increases the enzymatic activity of LIPG polypeptide; or an enhancer which increases the expression of LIPG gene. The invention relates also to methods for using the above compositions. In addition, the invention relates to a method for diagnosing a predisposition to lower cholesterol, a method for determining whether a test compound can inhibit the enzymatic reaction between LIPG polypeptide and HDL cholesterol, and methods for determining whether a test compound can enhance the enzymatic reaction between LIPG polypeptide and LDL or VLDL cholesterol.

Compositions and methods for effecting the levels of high density lipoprotein (HDL) cholesterol and apolipoprotein AI very low density lipoprotein (VLDL) cholesterol and low density lipoprotein (LDL) cholesterol

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Philadelphia, PA, United States of America

Daniel J Rader