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  1. 1. Therapeutic Angiogenesis: Protein and Gene Therapies offer Hope to Patients with Myocardial Ischemia Ryan McAuley Dept. of Biology Furman University Greenville, SC
  2. 2. <ul><li>Palo Alto Veterans Affairs Healthcare System </li></ul><ul><li>Stanford University School of Medicine Department of Cardiology </li></ul>
  3. 3. Outline <ul><li>Overview of Myocardial Ischemia: etiology, diagnosis, symptoms, and conventional treamtents </li></ul><ul><li>Angiogenesis: history and development </li></ul><ul><li>Overview of current studies </li></ul><ul><li>Results from clinical trials </li></ul><ul><li>Future Studies </li></ul>
  4. 4. Myocardial Ischemia <ul><li>Gr. ischein “to hold back” + haima “blood” </li></ul><ul><li>Caused by: </li></ul><ul><li>-Stenosis of coronary arteries </li></ul><ul><li>-Acute blockage </li></ul><ul><li>Coronary blood flow inadequate for maintaining cardiac function </li></ul><ul><li>Result: cardiac muscle is deprived of essential nutrients and gas exchange </li></ul><ul><li>Symptoms: most common is angina pectoris </li></ul>
  5. 5. Diagnosis <ul><li>Electrocardiogram (ECG) </li></ul><ul><li>Exercise Tolerance Test (ETT) </li></ul><ul><li>Myocardial Perfusion Imaging </li></ul>
  6. 6. Treatment <ul><li>Complications include: myocardial infarction, cardiac arrhythmias, CHF, and low quality of life </li></ul><ul><li>Pharmacotherapy: combination of drugs </li></ul><ul><li>-antiplatelet agents </li></ul><ul><li>-antithrombotic drugs </li></ul><ul><li>-lipid-lowering drugs </li></ul><ul><li>-anti-anginal drugs </li></ul><ul><li>Invasive Therapies: </li></ul><ul><li>-CABG and PCI </li></ul>
  7. 7. Limitations <ul><li>Symptoms not relieved by drugs </li></ul><ul><li>Patient is not good candidate for invasive procedures </li></ul>
  8. 8. Angiogenesis <ul><li>Offers hope to these “no-option” patients. </li></ul><ul><li>Current clinical trials to assess safety and efficacy for FDA approval </li></ul><ul><li>Definition: extension of already formed primitive blood vessels by budding of new capillaries through proliferation and migration of endothelial cells </li></ul><ul><li>Takes place during embryonic development and combined with vasculogenesis, is responsible for development of the circulatory system </li></ul><ul><li>Naturally-occurring process in adults that is prompted by hypoxia or ischemia after occlusion of an artery </li></ul>
  9. 9. Meet the Growth Factors <ul><li>Fibroblast Growth Factor (FGF) </li></ul><ul><li>-Peptide Family </li></ul><ul><li>-Cross-species homology </li></ul><ul><li>-Targets: endothelial cells, smooth muscle cells, fibroblasts, myocytes, and some tumor cells </li></ul><ul><li>Vascular Endothelial Growth Factor (VEGF) </li></ul><ul><li>-Glycoprotein Family </li></ul><ul><li>-Targets endothelial cells exclusively </li></ul>
  10. 10. The Process <ul><li>Hypoxic conditions </li></ul><ul><li>VEGF upregulation occurs within 6 hours due to: </li></ul><ul><li>-stabilization of mRNA coding </li></ul><ul><li>-increased transcription due to activation of Hypoxia-Inducible Factor-1 (HIF-1) in the promoter region of VEGF </li></ul><ul><li>If this is a naturally-occurring process, why do pts. still have disabling chest pain?? </li></ul>
  11. 11. The Problem <ul><li>Animal studies have shown impaired angiogenesis and reduced endothelial cell viability in older animals </li></ul><ul><li>Decreased angiogenic activity also noted in diabetic and hypercholesterolemic mice </li></ul><ul><li>Since many patients. with myocardial ischemia have other health problems such as these, angiogenesis does not sufficiently improve coronary blood flow </li></ul><ul><li>Don’t be sad… </li></ul>
  12. 12. BE GLAD!!! <ul><li>In all of these cases VEGF supplementation produced favorable results with regards to </li></ul><ul><li>and </li></ul>Endothelial Cell Response Growth
  13. 13. Early Work <ul><li>Discovered by Folkman in early 1970’s </li></ul><ul><li>Link between vascular GF’s and neovascularization associated with tumor growth </li></ul><ul><li>In 1983, Kumar et al. studied the presence of an “angiogenesis factor” in the human heart following MI </li></ul><ul><li>Mid-1980’s: several polypeptide growth factors associated with angiogenesis identified and purified </li></ul><ul><li>As a result, animal and human studies could be expanded </li></ul><ul><li>Pre-clinical animal studies used an ameroid constrictor to gradually occlude one of the coronary arteries. </li></ul><ul><li>Pigs, dogs, and rabbits have been used for models of therapeutic angiogenesis </li></ul>
  14. 14. Animal Studies <ul><li>VEGF and FGF administered in various amounts and by different routes </li></ul><ul><li>Effectiveness measured by many means including: </li></ul><ul><li>-size and number of vessels </li></ul><ul><li>-measurement of coronary blood flow </li></ul><ul><li>-quantitation of endothelial cell markers </li></ul><ul><li>Positive results for protein and genes, but a few problems </li></ul>
  15. 16. Current Studies <ul><li>Endpoints </li></ul><ul><li>Gene Therapy Vs. Protein Therapy </li></ul><ul><li>Administration Route </li></ul><ul><li>Dosage </li></ul><ul><li>-Placebo? </li></ul>
  16. 17. Common Endpoints <ul><li>Change in total ETT time at baseline and after treatment </li></ul><ul><li>Frequency of angina: # of doses of nitro per week </li></ul><ul><li>Perfusion Imaging: MRI, angiography </li></ul>
  17. 18. ETT Evaluation
  18. 19. ST Segment
  19. 20. ST Segment Depression = ST segment depression Normal Myocardial Ischemia
  20. 21. Data Points from ETT <ul><li>Time to onset of angina </li></ul><ul><li>Time to >1mm change in ST segment </li></ul><ul><li>Measurement of HR, BP, and ST segment depression at maximal exercise (angina pain rated as a 3 out of 4 or exhaustion) </li></ul><ul><li>Measurement of ST segment depression at 1, 3, and 5 minutes recovery </li></ul>
  21. 22. Overview of Current Studies <ul><li>Comparisons: </li></ul><ul><li>-Protein Therapy Vs. Gene Therapy </li></ul><ul><li>-Administration Route </li></ul><ul><li>-Dosage </li></ul><ul><li>FDA approval: </li></ul><ul><li>-Phase I to determine safety/feasibility </li></ul><ul><li>-All subsequent phases must include placebo group to determine efficacy </li></ul>
  22. 23. Physical Properties of GF <ul><li>GOAL: High exposure to coronary vessels, Low systemic exposure </li></ul><ul><li>Protein Therapy: </li></ul><ul><li>-recombinant form of FGF or VEGF </li></ul><ul><li>Gene Therapy: </li></ul><ul><li>- VEGF or FGF inserted into a viral vector </li></ul><ul><li>-Naked DNA plasmid encoding for transcription of VEGF or FGF </li></ul>
  23. 24. <ul><li>Exposure to GF </li></ul><ul><li>Need for repeat dose </li></ul><ul><li>Readministration </li></ul><ul><li>Exposure to foreign genetic material </li></ul><ul><li>Systemic Exposure </li></ul>Protein Therapy Gene Therapy Characteristic Short-lived Prolonged More likely Less likely Easier Potential risk for inflammatory response if viral vector used No Yes Short-term, Long-term, but high level but low level
  24. 25. Administration Routes <ul><li>GOAL: Least invasive procedure that allows for Optimal uptake of GF’s </li></ul><ul><li>Many have been used </li></ul><ul><li>Most common are Intracoronary and Intramyocardial </li></ul>
  25. 26. Dosage <ul><li>GOAL: Dose is Large enough to be effective in coronary arteries, but Small enough that systemic exposure is not a concern </li></ul><ul><li>Protein Therapy: µg/kg or ng/kg </li></ul><ul><li>Gene Therapy: </li></ul><ul><li>-number of viral particles </li></ul><ul><li>-DNA plasmids in units of µg </li></ul><ul><li>Escalating dose groups to determine how side effects and effectiveness are related to the amount of GF administered </li></ul><ul><li>Placebo group shows objective comparison to treatment group and randomization removes physician bias </li></ul>
  26. 27. Results of Phase I Studies <ul><li>In all studies, favorable results were reported </li></ul><ul><li>Increased myocardial perfusion shown on MRI and angiography, increased ETT time compared to baseline, and decreased angina </li></ul><ul><li>However, small sample size, lack of placebo group, and nonrandomization result in poor predictive value </li></ul>
  27. 28. Rosengart et al. 1999 <ul><li>n=21 </li></ul><ul><li>Randomized: No </li></ul><ul><li>Angiogenic Factor: VEGF 121 viral vector </li></ul><ul><li>Administration Route: Intramyocardial </li></ul><ul><li>Results: Improved angiography results, increased exercise time, decreased angina </li></ul>
  28. 29. Results of Phase II Studies <ul><li>Not consistently significant </li></ul><ul><li>Dramatically demonstrate normalizing effect of placebo group </li></ul>
  29. 30. Kleiman and Califf 2000 FIRST multicenter study <ul><li>n=337 total in 3:1 ratio of active agent to placebo </li></ul><ul><li>Randomized: Yes </li></ul><ul><li>Angiogenic Factor: FGF-2 </li></ul><ul><li>Administration Route: Intracoronary </li></ul><ul><li>Results: </li></ul><ul><li>-No significant improvement in exercise time or stress nuclear perfusion imaging at 90 days </li></ul><ul><li>- Less angina in treatment group (P=0.057) </li></ul><ul><li>- Trend toward greater improvement in older and more symptomatic pts. </li></ul>
  30. 31. What Happened? <ul><li>Small sample size </li></ul><ul><li>Insensitive end-points </li></ul><ul><li>Single-administration of GF </li></ul><ul><li>Acute myocardial ischemia in animal models Vs. chronic myocardial ischemia in humans </li></ul>
  31. 32. So… <ul><li>While angiogenesis has great potential, more research needed </li></ul><ul><li>Short term goal: prove efficacy in large-scale, placebo-controlled trials </li></ul><ul><li>Determine long-term safety by addressing concerns… </li></ul>
  32. 33. Some Clinical Concerns <ul><li>Cancer </li></ul><ul><li>Abnormal vascular growth in non-target tissues </li></ul><ul><li>Immune consequences of using viral vectors with foreign genetic material </li></ul><ul><li>Risks associated with local myocardial delivery </li></ul><ul><li>Note: these concerns have not all been validated in research and the list will most likely evolve in the future </li></ul>
  33. 34. The Future <ul><li>Variations on the theme that increased exposure to GF’s yields optimal vascularization </li></ul><ul><li>Multiple doses and/or sustained release of recombinant proteins </li></ul><ul><li>Administration of multiple GF’s </li></ul><ul><li>Administration of HIF-1 </li></ul><ul><li>Autologous bone marrow injection </li></ul>
  34. 35. THE END <ul><li>Special thanks to Dr. Thompson for her support and guidance through this entire project. </li></ul><ul><li>To Victor Froelicher, MD and Jonathan Myers, PhD for allowing me the opportunity to work with them and for their help with my paper. </li></ul><ul><li>To my uncle Paul McAuley, PhD for the “referral” to the aforementioned Docs. </li></ul><ul><li>To Soon-to-be-Dr. Schammel for her encouragement and technological assistance. </li></ul><ul><li>To Dr. Turgeon for her help and enthusiasm. </li></ul><ul><li>And finally, to Dean Charles Brock, PhD for allowing Furman students the opportunity to participate in internships such as these through Furman Advantage funding. </li></ul>