Understanding and Curing RRP: a genetic undertaking Allegheny General Hospital Pittsburgh, PA Center...

Understanding and Curing RRP: a genetic undertaking

Allegheny General Hospital

Pittsburgh, PA

Center for Genomic Sciences

Allegheny Singer Research Institute

Farrel J. Buchinsky, MD

Pediatric Otolaryngologist

Interest Piqued “Cool” Surgery Ridiculous outcome

Because kept coming back

What is the cause of RRP?

Necessary Is it sufficient?

Many exposed Only few get the disease

Spectrum of Understanding

Genetics

Disease

Cell Biolog

y

Epidemiology

Understanding increases probability of developing cure or eradication

Life

Genetics at its simplest

Genes

Genes

Center for Genomic SciencesAllegheny General Hospital, Pittsburgh

We each have two sets of genes

TDT

Mother Father

C DBA

C DA B

Result of all possible zygotes

A C B C A D B D

Transmitted

Untransmitted

A B

A x

B y

From who?

Funding

Acquisition

Mouthwashspecimens

No HospitalsNo Doctors

Enrolment of peoplewith RRP and their

parentsSatelliteDesign

Support-GroupDesign

Papilloma and BloodSpecimens

Coordinating CenterDr. Farrel Buchinsky

Ms. Marilyn SmithCenter for Genomic SciencesAllegheny-Singer Research

Institute

IRB

IRB

IRB

IRB Approved

Allegheny General Hospital, Pittsburgh Children's Hospital of the King's

Daughters, Norfolk Children's Hospital of Wisconsin,

Milwaukee Children's National Medical Center,

Washington Cincinnati Children's Hospital Medical

Center Johns Hopkins Children's Center,

Baltimore Children's Medical Center of Dallas Children's Hospital of Philadelphia SUNY Upstate Medical Center,

Syracuse Hospital for Sick Children, Toronto Children's Hospital of Alabama,

Birmingham Pending

University of California - San Francisco Children's Hospital and Regional

Medical Center, Seattle

EnrolmentPatient Enrolement

0

10

20

30

40

50

60

70

80

90

Jan-03 Apr-03 Jul-03 Oct-03 Jan-04 Apr-04 Jul-04 Oct-04 Dec-04 Apr-05 Jul-05 Oct-05 Dec-05

Ru

nn

ing

To

tal

Count Institution Doctor

15 Cincinnati Children's Hospital Medical Center Charles Myer

12 Children's Medical Center of Dallas John McClay

11 Children's Hospital of the King's Daughters Craig Derkay

10 The Hospital for Sick Children Paolo Campisi

9 Children's National Medical Center Sukgi Choi

7 Children's Hospital of Wisconsin Stephen Conley

3 Johns Hopkins Children's Center David Tunkel

2 Children's Hospital of Philadelphia Lisa Elden

13 from Patient Support Groups

Which gene or genes 3x109 bases Candidate Gene Approach Genomic Scan Approach

Epidermodysplasia Verruciformis Rare, autosomal recessive, skin disease Abnormal susceptibility to specific HPVs (5 and 8)

persistent lesions that do not clear virus 4 specific mutations found in EVER1

Dr. Mark Naylor, Electronic Textbook of Dermatology

EVER1 Mutations not present in RRP

Allele Specific PCR

RFLP

Positive control

Positive control

First 60

Maybe somewhere else in EVER1

Ramoz

Tate

Tate

Ramoz

Looking at about 20 SNP markers in area

Candidates MHC Innate Immunity

Toll-like receptors Known Cell Biology Interactions

E5 inhibits H+ATPase from acidifying vesicles Other Diseases

Epidermodysplasia Verruciformis Cervical Cancer

Whole Genome

96 humans at a time 6000 SNPs, more

coming

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illumiCode #561

illumiCode #217

illumiCode #1024

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A/A T/T A/T

Challenge I Distributed, replicated with random noise

IRB

Challenge II Need many more

patients Support Groups International www.rrpgenetics.org

More Patients + Parents More Data Believable Conclusions Understanding

Acknowledgments CGS

Garth Ehrlich, Chris Post Joseph Donfack, Marilyn

Smith, Fen Hu Earliest Collaborators

Craig Derkay, Suzanne Leal Patient Support Groups

Michael Green, Bill Stern

fbuchins@wpahs.org

cell: (412) 779-1073