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Gene Therapy for Vascular Disease - State of the Art ?

Gene Therapy for Vascular Disease - State of the Art ?. K. Craig Kent M.D. Angiogenesis for lower extremity vascular disease. Angiogenesis. Arteriogenesis. Vascular Endothelial Growth Factor (VEGF) Fibroblast Growth Factor (FGF) Hepatocyte growth Factor (HGF)

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Gene Therapy for Vascular Disease - State of the Art ?

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  1. Gene Therapy for Vascular Disease - State of the Art ? K. Craig Kent M.D.

  2. Angiogenesis for lower extremity vascular disease

  3. Angiogenesis Arteriogenesis

  4. Vascular Endothelial Growth Factor (VEGF) Fibroblast Growth Factor (FGF) Hepatocyte growth Factor (HGF) Insulin-like growth factor Granulocyte colony stimulating factor Hypoxia inducible factor Kallikrein Angiopoietin Transforming growth factor Angiogenic Growth Factors

  5. Therapeutic Angiogenesis

  6. Clinical Trials

  7. Conclusion Potential is tremendous ! Many new innovations ! Another few years away !

  8. Application of Angiogenic Therapy FormRoute * Protein * Intravenous * DNA * Intraarterial Viral * Intramuscular Naked

  9. Clinical Trials - angiogenesis • Isner et. al. • NYPH • TRAFFIC • AVENTIS • TACT

  10. Therapeutic Angiogenesis for Lower Extremity Ischemia New York Presbyterian Hospital FDA approved Phase 1 double blinded placebo controlled clinical trial Growth factor - VEGF 121 Form - Replication deficient adenovirus Route -Intramuscular injections Ascending dosing schedule, 4 x 108 - 4 x 1010 pfus

  11. New York Presbyterian Hospital Claudication - 20 Patients Limb Threat - 20 Patients

  12. New York Presbyterian Hospital Results No adverse events: adenoviral VEGF is safe No statistically signficant benefit in either group

  13. (TRAFFIC)Therapeutic Angiogenesis with FGF-2 (protein) For Intermittent Claudication • Growth factor - recombinantFGF-2 • Form - protein • Route -Intraarterial Phase II, multicenter, randomized, double blind, placebo controlled trial Intermittent claudication

  14. Day 0 Day 30 Group # 1 Placebo Placebo Group # 2 FGF Placebo Group # 3 FGF FGF TRAFFIC Patients:190 Inclusion: Claudication, ABI < 0.8 Route:Intra-arterial Groups: METHODS

  15. TRAFFIC Primary Endpoint Peak walking time Secondary Endpoints Claudication onset time Ankle brachial index Quality of life

  16. Results - Primary Endpoint Peak Walking Time (90 days) p= 0.026 1.77 min 1.54 min .6 min Placebo Single dose Double dose

  17. Secondary Endpoint Change in peak walking time at 180 days p=N.S Placebo Single dose Double dose

  18. Secondary Endpoints • No difference at 90 or 180 days • Claudication onset time • Quality of life • Walking impairment questionnaire and SF-36

  19. Traffic: Conclusions • Intra-arterial infusion of rFGF-2 is safe (albeit hypotension and proteinuria were observed) • Statistically significant increase in PWT at 90 days • Clinical relevance - unlikely

  20. Aventis - Phase I Trial Comerota et al. • Growth factor - FGF • Form - naked DNA • Route -Intramuscular Phase I, multicenter nonrandomized trial limb threatening ischemia

  21. Aventis - Phase I • Patients: n=51. • Inclusion: Ischemic rest pain, ABI < 0.4 • Dosage:500, 1000, 2000, 4000 ug NV1FGF METHODS

  22. Aventis - Phase I Results - Safety • No serious adverse events attributable to FGF • No pathological angiogenesis

  23. Results *** ** **p=.007 ***p=.005 1 2 3 7 11 23

  24. Results *** ** * * * * p<.03 ** p=.001 ***p=.0001 1 2 3 7 23

  25. Results * ** ** ** *p=.04 **p=.0001 1 2 3 7 11 23

  26. Results * P < .01 1 2 3 7 11 23

  27. Aventis phase I trial Limitations: • Number of patients small (n =15@ 6 mo) • No randomization phase 2 is now completed - awaiting results

  28. Stem Cells(Endothelial Progenitor Cells) Angiogenesis

  29. Bone Marrow Endothelial Progenitor Cell injection Ischemic Tissue Peripheral Blood VEGF FGF cytokines Capillary formation

  30. TACT Investigators (therapeutic angiogenesis using cell transplantation) Lancet - August 2002 • Methods: • Bone marrow aspirate (500 cc) • Monocytes isolated and concentrated into (30 cc) • Injection into the gastrocnemius muscle (3 hrs) • 40 injections • 26 gauge needle • 1.5 cm deep • 0.75cc each

  31. Results TACT Total legs injected = 45 weeks 0 4 16 ABI.35 .42 .46 TcO2(mm Hg)28 46 45 Pain free (min) walking time1.3 3.6 3.7

  32. TACT Results Total legs injected = 45 Relief of rest pain complete 22 partial 15 Prevention of toe amputation 15/20 Improvement of ischemic ulceration 6/10 Increase in collaterals by angiography 27/45

  33. Stem cell therapy for angiogenesis is the new frontier

  34. Where to Inject ?How deepHow many Unknown

  35. Protein ?Naked DNA ?Viral Vector ?Stem cells ? Unknown

  36. Concentration of protein, DNA or stem cells ? Unknown

  37. Does it work ? Unknown

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