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Cedars-sinai Medical Center

Tripathi Rajavashisth

Prediman Krishan Shah

Moshe Arditi

Compositions and methods included herein describe the treatment of atherosclerosis and other vascular diseases such as thrombosis, restenosis after angioplasty and/or stenting, and vein-graft disease after bypass surgery, by inhibition of the expression or biologic activity of the toll-like receptor 4 (TLR4) and/or myeloid differentiation factor 88 (MyD88). TLR4 cell signal transduction is at least partially responsible for the manifestation, continuation, and/or worsening of atherosclerosis and other forms of vascular disease. The present invention provides several means with which to inhibit this signal transduction pathway by affecting the biological activity of the TLR4 receptor and/or MyD88.

Methods for treating vascular disease

Described herein are methods of inhibiting M-CSF activity, and, in particular, M-CSF/c-fms dependent cell signaling. In a first embodiment of the invention, one administers to a mammal viral vectors that deliver genes experessing antisense c-fms RNA; in a second embodiment, one induces in vivo production of a high-affinity soluble c-fms protein that competes for non-bound M-CSF; in a third embodiment, one administers a ribozyme-viral vector against c-fms mRNA; and in a fourth embodiment, one administers oligodeoxynucleotides that inhibit expression of c-fms gene product. The methods may be used to treat any disease in which M-CSF activity plays a role, and are particularly effective in treating and preventing atherosclerosis. Embodiments of the present invention are directed primarily, but not exclusively, to a method for treating and preventing cardiovascular disease by inhibiting receptors to M-CSF. Other embodiments of the present invention include any and all biologic and/or pathobiologic phenomena mediated in whole or in part by M-CSF signaling through its receptor. Pathobiologic phenomena include, but are not limited to, disease entities such as osteoporosis, Alzheimer's disease, diabetes mellitus (Type 1 and/or Type 2), infectious diseases, cancer, and inherited disorders characterized by defects in one or more components in the M-CSF signaling pathway.

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El Camino Village, CA, United States of America

Tripathi Rajavashisth