Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1999-06-07
2001-10-16
Davenport, Avis M. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S002600, C514S014800, C514S016700, C514S021800, C530S300000, C530S324000, C530S327000, C530S328000, C530S329000, C424S185100
Reexamination Certificate
active
06303573
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to the fields of molecular medicine and drug and gene delivery and, more specifically, to novel compositions for treating cardiovascular disease.
2. Background Information
The term atherosclerosis is used to describe thickening and inelasticity of vessel walls or arteries as a consequence of atheroma. Atherosclerosis and its sequelae constitute the most common and important cause of disease and death in the western world, accounting for 50% of all deaths in the west.
In normal hearts, vessel walls are composed of an endothelial cell lining that is tightly juxtaposed to a medial layer of vascular smooth muscle cells with an over layer of connective tissue. The endothelial cell lining is ideally situated at the interface between the blood and the vessel wall to transduce signals, with endothelial cells controlling the homeostatic balance of the vessel through the production of factors regulating vessel tone, coagulation state, cell growth, cell death, and leukocyte trafficking. Vascular smooth muscle cells maintain the contractile tone of the blood vessel in response to vasoactive agents and release cytokines and other growth factors. In conjunction with fibroblasts, the smooth muscle cells produce extracellular matrix proteins and proteases that determine vessel structure. Occlusive vascular disease, the most common form of which is atherosclerosis, is characterized by an abnormal accumulation of vascular smooth muscle cells, inflammatory cells, and extracellular matrix proteins within the intimal space between the endothelial lining and the medial layer (neointima formation).
Therapies for atherosclerosis generally prevent, arrest or reverse the process of neointima formation or stimulate new blood vessel formation (angiogenesis). It is rare, however, that a drug or other agent for treatment of atherosclerosis targets only coronary vessels. More commonly, systemic administration results in undesirable side effects due, for example, to generalized toxic effects throughout the entire body. For example, vascular endothelial growth factor (VEGF), a key regulator of angiogenesis that stimulates endothelial cell proliferation, promotes the formation of new vessels, thereby increasing blood flow to ischemic tissue and relieving vascular disease. However, VEGF also can promote nonspecific mitogenesis and potentiate angiogenesis-driven diseases such as diabetic retinopathy, and certain tumors. Similarly, systemic administration of the angiogenic stimulator fibroblast growth factor can cause severe side effects due to its lack of specificity for heart tissue. Unfortunately, such side effects, including repetitive episodes of hypertension, limit the utility of this therapy.
As the internal lining of blood vessels, the endothelium is the first cell type encountered by a circulating therapeutic substance. Endothelial cells therefore provide a target for selectively directing a therapeutic substance to cardiac tissue. Such selective targeting of a therapeutic agent to cardiac endothelium would reduce or eliminate the risk of unwanted side effects such as systemic toxicity or malignant transformation. Selective targeting of a therapeutic substance to cardiac endothelium also would effect a high local concentration of the substance, thereby reducing the dosage required for effective treatment.
Thus, a need exists to identify molecules that selectively bind to cardiac endothelium in vivo. Such molecules would be particularly useful for selectively targeting therapeutic agents to the heart for treatment of atherosclerosis. The present invention satisfies this need and provides related advantages as well.
SUMMARY OF THE INVENTION
The present invention provides an isolated heart homing peptide that selectively homes to cardiac tissue. An isolated heart homing peptide of the invention can contain, for example, the amino acid sequence GGGVFWQ (SEQ ID NO: 2); HGRVRPH (SEQ ID NO: 3); VVLVTSS (SEQ ID NO: 4); CLHRGNSC (SEQ ID NO: 9); or CRSWNKADNRSC (SEQ ID NO: 10), or a functionally equivalent modification thereof. An isolated heart homing peptide of the invention can have, for example, a length of less than forty amino acids or a length of less than fifteen amino acids.
Also provided by the invention is a conjugate composed of a heart homing peptide linked to a moiety, where the heart homing peptide contains the amino acid sequence GGGVFWQ (SEQ ID NO: 2); HGRVRPH (SEQ ID NO: 3); VVLVTSS (SEQ ID NO: 4); CLHRGNSC (SEQ ID NO: 9); or CRSWNKADNRSC (SEQ ID NO: 10), or a functionally equivalent modification thereof. In a conjugate of the invention, the moiety can be, for example, a therapeutic agent, detectable agent or tag. Exemplary therapeutic agents are provided herein as vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF).
The present invention further provides a method of treating a cardiovascular disease in a subject by administering a conjugate that contains a heart homing peptide linked to a therapeutic agent, where the heart homing peptide contains the amino acid sequence GGGVFWQ (SEQ ID NO: 2); HGRVRPH (SEQ ID NO: 3); VVLVTSS (SEQ ID NO: 4); CLHRGNSC (SEQ ID NO: or CRSWNKADNRSC (SEQ ID NO: 10), or a functionally equivalent modification thereof. The methods of the invention are useful for treating a variety of cardiovascular diseases including atherosclerosis and restenosis.
Also provided by the invention is an isolated peptide that selectively homes to ischemic tissue. Such a peptide, referred to herein as an ischemic tissue selective peptide, can contain, for example, the amino acid sequence CRSWNKADNRSC (SEQ ID NO: 10), or a functionally equivalent modification thereof. In one embodiment, the isolated ischemic tissue selective peptide is not an antibody or antigen-binding fragment thereof. In other embodiments, the ischemic tissue selective peptide has a length of less than forty amino acids or a length of less than fifteen amino acids. An ischemic tissue selective peptide of the invention can be useful in the form of a conjugate to selectively deliver a linked moiety to ischemic tissue.
The invention also provides methods of treating ischemic disease in a subject. The methods involve administering a conjugate including an ischemic tissue selective peptide that selectively homes to ischemic tissue, where the peptide is linked to a moiety.
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MacKenna Deidre A.
Ruoslahti Erkki
Campbell & Flores LLP
Davenport Avis M.
The Burnham Institute
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