Vascular Ehlers-Danlos syndrome: P lacing recent studies into context

1. Vascular Ehlers-Danlos syndrome: Placing recent studies into context Mitzi L. Murray, MD, MA EDNF Annual Learning Conference August 10, 2012

2. For me context is the key - from that comes the understanding of everything. Kenneth Noland (American artist 1924-2010) Heat, 1958

3. Objectives • Review different types of medical research • Discuss genotype-phenotype correlations in vEDS focusing on recent COL3A1haploinsufficiency study • Discuss recent clinical trial of celiprolol • Propose future directions

4. Objectives • Review different types of medical research • Discuss genotype-phenotype correlations in vEDS, focusing on COL3A1haploinsufficiency • Discuss recent clinical trial of celiprolol • Propose future directions Provide context

5. EDS type IV – the vascular type Clinical Features • Risk of arterial, organ & pregnancy complications • Variability within and between families Cause and diagnosis • Due to mutations (changes) in the gene COL3A1 • Diagnosis • Clinical • Biochemical (Protein studies of type III collagen) • Molecular (Genetic)

6. Questions yet unanswered Why is there variability? What factors contribute to risk for complications? Should we perform surveillance studies? How? Can medications/treatments reduce risk? Can we change the course of the condition? How are complications best managed?

7. What is medical research? • Focuses on human health and disease • Can mean many different things

8. Medical Research Primary Secondary Basic Clinical Epidemiological

9. Medical Research Primary Secondary Basic Clinical Epidemiological Animal studies Doxycycline in mouse model of vEDS Cell studies Allele-specific siRNA in vEDS Genetic studies

10. Experimental Medication Trials Interventions Observational Natural History Genotype-Phenotype Interview, Qualitative, etc Medical Research Primary Secondary Basic Clinical Epidemiological

11. Medical Research Primary Secondary Basic Clinical Epidemiological Population frequency Environmental influences

12. Points about research to consider • A single study rarely answers the question definitively • Important to prove a result is replicable • Findings may not be generalizable • Premature translation of research findings into the clinical realm can be harmful • Ex: autism and vaccines

14. “One hypothesis to explain the failure to identify this class of mutations is that the phenotype caused by COL3A1 haploinsufficiency differs, with respect to its severity or its symptomatic range, from the usual presentation of EDS type IV…”

15. 2 Copies of the COL3A1 gene Each gene copy makes protein chains Three protein chains come together to form type III collagen

18. Quality vs. quantity…

19. Clinical observational study • 19 of 508 families with vEDS • 54 total affected persons • 19 index patients • 35 affected family members • Major complications • 18/19 index patients, 10/35 family members • All major complications were arterial Genetics in Medicine 13(8); 2011.

20. Age distribution

22. Conclusions from this study • Most individuals with null mutations have different clinical course • Longer life expectancy • Later age of first complication • Complications primarily vascular • Less frequently have minor clinical features • Limitations • Relied on available medical history • Families identified because of complication, risk of complications likely over-estimated

23. Implications? • For those with null mutations, information may be somewhat reassuring • At this time, my clinical recommendations are the same for families with null mutations • Future interventional studies should take mutation type (protein altering vs. null) into account in design

25. Directions for future research Basic research • Further explore use of animal models in vascular EDS research • Further studies using allele-specific siRNA • Better understanding the role of type III collagen in more come forms of aneurysms and dissections.

26. Directions for future research Clinical research • Observational • Ongoing NIH study on natural history • Pregnancy outcomes in vascular EDS • Interventional • Doxycycline in humans? • Is celiprolol study replicable in study of only persons with COL3A1 mutations? • Imaging surveillance and intervention studies?

27. Directions for future research Epidemiological research • Are the identifiable environmental risk factors for complications? • How common is vascular EDS? - especially considering many families with null mutations may be unidentified

28. In summary • We continue to make progress but there is much much more to be learned • We need to continue working together in research efforts to improve the clinical care for individuals and families with vascular EDS

29. Thank you!Individuals and families living with Ehlers-Danlos syndrome or other heritable connective tissue disorders. Collagen Diagnostic Laboratory Peter Byers Ulrike Schwarze Melanie Pepin DruLeistreitz Shawna Pyott Jennifer Schleit Margaret Yang Diana ChenThaoTran Lily Hoang Stephanie Karczynski Arnold AltamiraDennis Sarroza Alex Launderdale Susan Stowers Barbara Kovacich Catherine Nguyen Dept of Pathology Dept of Medicine, Div of Medical Genetics Freudmann Fund for Ehlers-Danlos Syndrome Research

30. References Briest, et al. Doxycycline ameliorates the susceptibility to aortic lesions in a mouse model for the vascular type of Ehlers-Danlos syndrome. J PharmacolExpTher. 2011;337(3):621-627. Leistritz, et al. COL3A1 haploinsufficiency results in a variety of Ehlers-Danlos syndrome type IV with delayed onset of complications and longer life expectancy. Genet Med. 2011;13(8):717-22. Muller, et al. Allele-specific siRNA knockdown as a personalized treatment strategy for vascular Ehlers-Danlos syndrome in human fibroblasts. FASEB J. 2012;26(2):668-77. Pepin, et al. Clinical and genetic features of Ehlers-Danlos syndrome type IV, the vascular type. N Engl J Med. 2000;342(10):673-80. Ong, et al. Effect of celiprolol on prevention of cardiovascular events in vascular Ehlers-Danlos syndrome: a prospective randomised, open, blinded-endpoints trial. Lancet. 2010;376(9751):1443-4. Tae, et al. Chronic Treatment with a Broad Spectrum MMP Inhibitor, Doxycycline, Prevents the Development of Spontaneous Aortic Lesions in the Mouse Model of Vascular Ehlers-Danlos Syndrome. J. PharmacolExpTher. 2012 Jul19. [Epub ahead of print]

31. Clinical interventional study • Goal: “to assess the preventive effect of celiprolol for major cardiovascular events in patients with vascular Ehlers-Danlos syndrome” Lancet 376; 2010

32. Who did they study? 1 major + 2 minor OR 4 minor criteria Major Personal or first degree relative history of arterial rupture or dissection Personal or first degree relative history of uterine or intestinal rupture Known COL3A1 mutation Minor Characteristic appearance Acrogeria Club foot Small joint hypermobility Tendon rupture Varicose veins AV fistula Pneumothorax Recessed gums Absence of inferior frenula

33. Enrolled 53 individuals 25 received celiprolol 28 received no treatment Observe rate of complications in both groups over 5 year period or until complication event occurred

34. Findings • Study stopped short due to difference seen between groups and small number remaining without complications • Observed a 69% risk reduction in group treated with celiprolol without reduction in heart rate or blood pressure

35. Study limitations • COL3A1 testing was not done prior to enrollment • Treated group 12-13/25 (48-52%) • Untreated group 20/28 (71%) • Celiprolol did not have the expected effect on blood pressure • If beneficial, mechanism is unknown

36. Study conclusions “We suggest that celiprololmight be the treatment of choice for physicians aiming to prevent major complications in patients with vascular Ehlers-Danlos syndrome.” “…results in the mutated population must be assessed cautiously…”