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