Vascular Ehlers-Danlos syndrome: Placing recent

studies into context

Mitzi L. Murray, MD, MAEDNF Annual Learning Conference

August 10, 2012

For me context is the key - from that comes the understanding of everything.

Kenneth Noland

(American artist 1924-2010)

Heat, 1958

Objectives

• Review different types of medical research• Discuss genotype-phenotype correlations

in vEDS focusing on recent COL3A1 haploinsufficiency study

• Discuss recent clinical trial of celiprolol• Propose future directions

Objectives

• Review different types of medical research

• Discuss genotype-phenotype correlations in vEDS, focusing on COL3A1 haploinsufficiency

• Discuss recent clinical trial of celiprolol• Propose future directions

Provide context

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)

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?

What is medical research?

• Focuses on human health and disease• Can mean many different things

Medical Research

Primary Secondary

EpidemiologicalClinicalBasic

Medical Research

Primary Secondary

EpidemiologicalClinicalBasic

Animal studiesDoxycycline in mouse model of vEDS

Cell studiesAllele-specific siRNA in vEDS

Genetic studies

Medical Research

Primary Secondary

EpidemiologicalClinicalBasic

Observational

Natural History

Genotype-Phenotype

Interview, Qualitative, etc

Experimental

Medication Trials

Interventions

Medical Research

Primary Secondary

EpidemiologicalClinicalBasic

Population frequency

Environmental influences

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

“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…”

2 Copies of the COL3A1 gene

Each gene copy makes protein chains

Three protein chains come together to form type III collagen

Quality vs. quantity…

• 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.

Age distribution

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

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

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.

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?

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

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

Thank you!Individuals and families living with Ehlers-Danlos syndrome or other heritable connective tissue

disorders.

Collagen Diagnostic LaboratoryPeter Byers Ulrike SchwarzeMelanie Pepin Dru LeistreitzShawna Pyott Jennifer SchleitMargaret YangDiana Chen Thao Tran Lily Hoang Stephanie

KarczynskiArnold Altamira Dennis SarrozaAlex Launderdale Susan Stowers Barbara Kovacich Catherine Nguyen

Dept of PathologyDept of Medicine, Div of Medical Genetics

Freudmann Fund for Ehlers-Danlos Syndrome Research

ReferencesBriest, et al. Doxycycline ameliorates the susceptibility to aortic lesions in a mouse model for the vascular type of Ehlers-Danlos syndrome. J Pharmacol Exp Ther. 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. Pharmacol Exp Ther. 2012 Jul19. [Epub ahead of print]

• 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

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 appearanceAcrogeriaClub footSmall joint hypermobilityTendon ruptureVaricose veinsAV fistulaPneumothoraxRecessed gumsAbsence of inferior frenula

Enrolled 53 individuals

28 received no treatment25 received celiprolol

Observe rate of complications in both groups over 5 year period or until complication event occurred

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

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

Study conclusions

“We suggest that celiprolol might 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…”