Novel Peptides for Therapeutic Angiogenesis and lschemic Cardiovascular Diseases
Invention Novel peptides were identified that bind endothelial cells and induce angiogenesis. The peptides were demonstrated to induce proliferation, migration and vascularization of endothelial cells under hypoxic conditions and completely restored blood perfusion in ischemic tissues in an ischemic hind limb mouse model. The peptides were shown to operate by binding to membrane GRP78 (glucose regulated heat shock protein) inducing inhibition of hypoxia induced apoptosis in endothelial cells and cardiomyocytes. The discovered peptides originate from a random peptide library and from ADAM 15 metalloprotease sequence. They might be used as ligands to induce endothelial cell angiogenesis, and were demonstrated to induce angiogenesis in a VEGF- independent pathway as an alternate mode of angiogenesis that avoids pathological angiogenesis induced by VEGF.The Need Angiogenesis – the development of blood vessels – is an emerging area of much activity and promise. Defective angiogenesis underlies numerous common diseases such as cardiovascular diseases, ischemic coronary artery diseases, rhematoid arthritis, diabetic retinopathy, atherosclerosis, psoriasis and cancerous tumors. This market is estimated to soar to over $3 billion by 2007. Blocking angiogenesis is an advancing strategy in the treatment of cancer and additional diseases, while stimulation is under investigation as means of replacing blood vessels in the heart and peripheral arteries that have become blocked. The need for new molecular targets and approaches to treat these indications is manifest in the inadequacy of current therapy, and in the rising number of biotechnology and pharmaceutical companies involved in research and development programs focusing on angiogenesis.
Potential Applications Applications for angiogenesis stimulators include:
Ischemic vascular disease Coronary artery disease Advanced wound care Arteriosclerosis Retinopathy Applications for inhibitors of hypoxia induced apoptosis include:
Myocardial infraction Ischemic vascular disease
Advantages 1. Novel angiogenetic natural ligand peptides. 2. Allows induction of angiogenesis in a VEGF-independent pathway. 3. An alternate mode of angiogenesis, avoiding pathological angiogenesis induced by VEGF. 4. Prevent hypoxia induced apoptosis also in cardiomyocytes.
Stage Two families of peptides were developed, the initial one based on a phage display combinatory peptide library, while the second is derived from a natural protein ADAM15 a disintegrin and metalloprotease. The peptides might be used as either synthetic or natural ligands to induce endothelial cell angiogenesis. The selected peptides demonstrated activity in cultured cells, affecting endothelial cell proliferation, migration, sprouting of aortic rings, tube formation, angiogenic gene expression, as well as showing prevention of hypoxia induces apoptosis in cardiomyocytes.
In vivo evaluation, in an ischemic hind limb model was performed in 3 mouse models: C57/ Bl healthy mice, STZ induced diabetic mice and APOE knockout mice. In brief, Ischemia was created in the mouse left hind limb by ligation and excision of the femoral artery. Each mouse was treated by a single intramuscular injection with each of the tested peptides and the blood perfusion was measured using a Laser Doppler Imager.
The results demonstrate:
Increase in the blood perfusion ratio in mice treated with the novel peptides demonstrating 21 days post operation a complete recovery of the blood perfusion in the operated hind limb. Inhibition of apoptosis in the treated hind limbs seen in histological sections one week post operation. Increase in the mean number of capillaries in the legs treated with the novel peptides seen 7 days post operation and sustained for 21 days post operation.
Patent Two patent families are currently pending, covering composition of matter and the various applications. Tech Transfer Officer Dr. Tamar Raz Office: +972-3-6406580 Fax: +972-3-6406675 Mail: [email protected]
Type of Offer: Licensing
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