Novel Angiogenic Therapies Using PR39 and Syndecan Proteins (BIDMC 101)

Category:    Therapeutics - Drugs

KeyWords:  Angiogenesis;  Peptide;  Vascular/Thrombosis;  

BIDMC ID:    101

Abstract:

Background: Ischemic heart disease remains the leading cause of morbidity and mortality in the Western hemisphere. Current management of myocardial ischemia includes surgical procedures such as coronary artery bypass grafting and percutaneous transluminal coronary angioplasty. Despite advancement in the treatment of myocardial ischemia, there remains a need for alternative treatments as a significant number of patients continue to have refractory congestive heart failure and ischemia. Therapeutic myocardial angiogenesis is the novel approach provided by this invention for the treatment of myocardial ischemia based on the use of pro-angiogenic growth factors to induce the development of new blood vessels to supply the myocardium at risk. PR39 is a macrophage derived peptide present in wound fluids as well as along the borders of acute myocardial infraction, and its appearance correlates with substantial changes in the heparan sulfate (HS) matrix. Dr. Simons has shown that macrophage derived peptide PR39, and its derivatives, inhibit the ubiquitin-proteasome-dependent degradation of hypoxia-induced factor1alpha (HIF1alpha) protein, resulting in accelerated formation of vascular structures in-vitro and increased myocardial vasculature in mice. Syndecan-4 is a transmembrane protein capable of carrying both HS chains extracellularly. Dr. Simons has also shown that bFGF binding to extracellular heparan sulfates attached to syndecan-4 core protein generates specific signaling through the cytoplasmic domain of this core protein that leads to alterations in cell growth, migration and adhesion. This mode of signaling constitutes a novel pathway of regulation of bFGF. Invention: The present invention describes two different methods for stimulation of angiogenesis. One method involves the delivery of PR39 or a PR39-derived oligopeptide to tissues or cells while the second method involves enhanced endothelial expression of syndecan-4 core protein fragments. The latter method includes prepared DNA sequence fragments of the syndecan-4 polypeptide that could be introduced into suitable expression vectors and delivered to endothelial cells. Dr. Simons has additionally shown that by maintaining the 183rd residue within syndecan-4 cytoplasmic domain in a non-phosphorylated state, stimulation of angiogenesis can also be obtained.

Inventor:   Michael Simons, MD

Commercial Opportunity:

Methods are provided to stimulate angiogenesis in a patient by the administration of PR39 or a PR39 derived peptide for the treatment of both coronary and peripheral vascular disease. Gene therapy approaches for the same that enhance the expression of syndecan proteins are also provided.

Competitive Advantages:

The angiogenic therapeutic approach provides a less invasive treatment of myocardial and peripheral vascular disease than existing surgical approaches

Related Publications:

Adenoviral PR39 improves blood flow and myocardial function in a pig model of chronic myocardial ischemia by enhancing collateral formation. Post et al (2005) Am J Physiol Regul Integr Comp Physiol. 290: 494.

Delayed arteriogenesis in hypercholesterolemic mice. Tirziu et al. (2005) Circulation
112: 2501.

PR39, a peptide regulator of angiogenesis. Li et al. (2000) Nature Med 6 (1): 40.
Fibroblast growth factor-specific modulation of cellular response by syndecan-4. Horowitz et al. (2002) J Cell Biol.

State of Development:

Proof of principle studies have been completed in a porcine model of chronic myocardial ischemia. Preliminary safety studies have been completed for PR39.

Related Technology URL:

http://www.med.yale.edu/intmed/faculty/simons.html

Patent Status:

US - 5 issued patents. Other US and counterpart foreign applications pending.
US 6,815,187 “Stimulation of angiogenesis via syndecan-4 cytoplasmic domain signaling pathway”

US 6,852,515 and 7,029,668 “Stimulation of angiogenesis via endothelial expression of syndecan-4 core proteins”

US 7,169,604 “Method of PR39 peptide mediated selective inhibition of IKB alpha”
US 7,202,212 “Method for PR39 peptide regulated stimulation of angiogenesis.

TVO Contact Info:
     Catherine M Lenich
     Senior Associate TVO
     clenich@bidmc.harvard.edu
     Phone: 617-667-0568   Fax: 617-667-0646

     Beth Israel Deaconess Medical Center
     Technology Ventures Office  Room: BR-0200
     330 Brookline Avenue
     Boston, MA 02215