understanding and curing rrp: a genetic undertaking allegheny general hospital pittsburgh, pa center...
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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
cell: (412) 779-1073