Transcript Understanding RRP: a genetic undertaking

Understanding and Curing
RRP: a genetic undertaking
Farrel J. Buchinsky, MD
Pediatric Otolaryngologist
Allegheny General Hospital
Center for Genomic Sciences
Pittsburgh, PA
Allegheny Singer Research Institute
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

Genetic
s
Cell
Biology
Understanding
increases probability of
developing cure or
eradication
Disease
Epidemiology
Life
Genetics at its simplest
Genes
Genes
Center for Genomic Sciences
Allegheny General Hospital, Pittsburgh
We each have two sets of genes
A B
C D
Mother
A
TDT
Father
C
B
D
Transmitted
A C
B C
A D
Result of all possible zygotes
B D
Untra
nsmitt
ed
A
A
B
y
B
x
From who?
Funding
Enrolment of people
with RRP and their
parents
Acquisition
Satellite
Design
SupportGroup
Design
IRB
IRB
No Hospitals
No Doctors
IRB
Coordinating Center
Papilloma and Blood
Specimens
Dr. Farrel Buchinsky
Ms. Marilyn Smith
Center for Genomic Sciences
Allegheny-Singer Research
Institute
Mouthwash
specimens
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
Enrolment
Patient Enrolement
90
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
80
70
Running Total
60
50
40
30
20
13 from Patient Support Groups
10
0
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
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
First 60
Allele Specific PCR
Positive
control
RFLP
Positive
control
Maybe somewhere else in EVER1
Ramoz
Tate
Tate
Ramoz
Looking at about 20
SNP markers in area
Candidates


MHC
Innate Immunity


Known Cell Biology Interactions


Toll-like receptors
E5 inhibits H+ATPase from acidifying vesicles
Other Diseases


Epidermodysplasia Verruciformis
Cervical Cancer
Whole Genome

A/A
illumiCode illumiCode
#217
#1024
/\/\/\/
/\/\/\/
illumiCode
#561
96 humans at a time
6000 SNPs, more
coming
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



Earliest Collaborators


Garth Ehrlich, Chris Post
Joseph Donfack, Marilyn
Smith, Fen Hu
Craig Derkay, Suzanne Leal
Patient Support Groups

Michael Green, Bill Stern
[email protected]
cell: (412) 779-1073