PRF By The Numbers Produced by Leslie B. Gordon, MD, PhD; Medical Director Please Do Not Reproduce Children’s Photographs Without Express Permission From PRF September 30, 2020
PRF By The Numbers
Produced by Leslie B. Gordon, MD, PhD; Medical Director
Please Do Not Reproduce Children’s Photographs Without Express Permission From PRF September 30, 2020
� Introduction and Collaborations 3 - 10
� Overview Data 11 - 19
� International Progeria Registry 20 - 23
� PRF Diagnostics Program 24 - 27
� PRF Cell & Tissue Bank 28 - 37
� PRF Medical & Research Database 38 - 42
� Weighing – In Program 43 - 46
� Clinical Trials 47 - 55
� PRF Grants Program 56 - 61
� Scientific Meetings and Workshops 62 - 65
� Publications 66 - 67
© 2020 The Progeria Research Foundation. All Rights Reserved. As of September 30, 2020
Table of Contents
ØPRF By The Numbers is a data sharing tool originating from
The Progeria Research Foundation’s programs and services.
ØWe translate information collected within our programs and
services, and develop charts and graphs which track our
progress from year to year.
ØThis allows you to assess where we’ve been, and the
improvements we’ve made for children with Progeria.
© 2020 The Progeria Research Foundation. All Rights Reserved. As of September 30, 2020
PRF By The Numbers: A Data Sharing Tool
Why Sharing Data Is Essential
ØAccording to the National Institutes of Health:
“data sharing is essential for expedited translation of research
results into knowledge, products, and procedures to improve
human health.”
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-032.html
Ø In other words, everyone benefits by knowing and learning as
much as possible about Progeria - the scientific and medical
communities, the public, and the children.
© 2020 The Progeria Research Foundation. All Rights Reserved. As of September 30, 2020
PRF By The Numbers…Here’s How It Works
ØWe take raw data collected through our programs and services, remove any personal information to protect the participant, and present it to you in a format that is engaging and informative.
Ø PRF programs and services include:
The PRF International Registry The PRF Diagnostics ProgramThe PRF Cell & Tissue BankThe PRF Medical & Research DatabasePRF Research GrantsScientific WorkshopsClinical Trial Funding and Participation
As of September 30, 2020© 2020 The Progeria Research Foundation. All Rights Reserved.
Our Target Audience
Ø PRF By The Numbers is intended for a broad array of users
Families and children with ProgeriaThe general public and nonscientists of all agesScientistsPhysiciansThe media
Ø This means that different types of slides will be of interest depending on who is looking at the information. We have designed this slide set so that you can pull out what is most important to you.
Ø We love suggestions - if you don’t see some facts and figures here that you think would be informative, please let us know at
As of September 30, 2020© 2020 The Progeria Research Foundation. All Rights Reserved.
PRF Programs: It All Starts With The Children
Our participants come from all over the world. They find
us through our outreach – the PRF
website, our publications,
television documentaries, their doctors, neighbors, friends and family.
Patient
Referral
Internation al Progeria
Registry
Diagnostics Program
Cell &TissueBank
Preclinical Research
Clinical Trials
Medical &ResearchDatabase
Weighing-InProgram
© 2020 The Progeria Research Foundation. All Rights Reserved. As of September 30, 2020
Program Collaborations For Success
PRF Cell & Tissue Bank Core Laboratory
PRF Medical & ResearchDatabase PRF Cell & TissueBank
PRF Diagnostics Program
PRF Diagnostics Program Sequencing Laboratory
PRF Cell Bank Submission: Immortalized Fibroblast CellLines
PRF Cell & Tissue Bank : iPS Cell Line Generation
PRF Cell & Tissue Bank: Lymphoblast Cell Line
Generation
PRF Clinical Trials
Non-HGPS Progeroid Patient Diagnosis
© 2020 The Progeria Research Foundation. All Rights Reserved. As of September 30, 2020
Our Program Collaborators
Our collaborating institutions are crucial to our ability to help children with Progeria.We are extremely grateful for these ongoing partnerships:
Brown UniversityLocation of The PRF Medical & Research DatabaseProgram IRB approval
Hasbro Children’s HospitalLocation of The PRF Cell & Tissue Bank Program IRB approval
PreventionGeneticsCLIA*-approved genetic sequence testing
Rutgers University Cell and DNA RepositoryCLIA*-approved lymphoblast generation and distribution
University of OttawaInduced Pluripotent Stem Cell (iPSC) CLIA*-approved generation and distribution
© 2020 The Progeria Research Foundation. All Rights Reserved. As of September 30, 2020
Our Clinical Trial Collaborators
Our collaborating institutions are crucial to our ability to help children with Progeria
Harvard University – Associated Hospitals:Boston Children’s Hospital Brigham and Women’s Hospital Dana Farber Cancer Institute
NIH – funded Clinical and TranslationalStudy Unit at Boston Children’s Hospital
© 2020 The Progeria Research Foundation. All Rights Reserved. As of September 30, 2020
As of September 30, 2020:
HGPS* in the United States:
Progeroid Laminopathies** worldwide:
Number of Living PRF-Identified Cases
Total Number of Children with Progeria Worldwide:
HGPS* worldwide: 128
18
51
Progeroid Laminopathies** in the United States: 13
179
*Children in the HGPS category have a progerin-producing mutation in the LMNA gene
** Those in the Progeroid Laminopathy category have a mutation in the lamin pathway but don’t produce progerin
© 2020 The Progeria Research Foundation. All Rights Reserved.
PRF-Identified Cases Reside In 53 CountriesAfghanistan Brazil Egypt Indonesia Japan Nepal Portugal South Korea Taiwan
Algeria Canada England Iran Kazakhstan Oman Russia Spain Tanzania
Argentina China France Iraq Libya Palestine-Gaza Saudi Arabia Sri Lanka Togo
Australia Colombia Germany Ireland Luxembourg Pakistan Serbia Suriname Turkey
Bangladesh Denmark Honduras Israel Malaysia Philippines South Africa Sweden Ukraine
Belgium Dominican Republic India Italy Mexico Poland Tajikistan USA
…and Speak 33 Languages
مؤسسةأبحاثلاشياخ
早衰症研究基金會
Progeria !रिसच फाउंडेशन 早老症研究財団
조로증연구재단
బాలుడబ లా కివయస స్ముదరుకండానేవృద్ా పా య్రూప్ంల నోకిివచ చ్ుటరసీ రె చ్ుఫ ండ షేన్
Progeria Araştırma Vakfı
прогерии исследовательский фонд
© 2020 The Progeria Research Foundation. All Rights Reserved. As of September 30, 2020
Arabic French Italian Marathi Russia Tagalog Ukrainian
Chinese German Japanese Nepali Serbian Tajik Urdu
Danish Hebrew Kannada Pashto Spanish Tamil Uzbek
Dutch Hindi Korean Polish Swahili Telugu
English Indonesian Malay Portuguese Swedish Turkish
Every Year Our Numbers Grow
Living Children PRF Has Identified with Progeria and The Countries They Reside In*
*When a child passes away, numbers are decreased. Numbers include those with HGPS and genetically confirmed Progeroid Laminopathies
16 17 17 18 19 19 22 26 29 30 31 2935 39 43 46 44 45 48 51 53
30 34 35 37 41 44 45 4652 54
7886
96
112
125134
144 144
155
166179
0
20
40
60
80
100
120
140
160
180
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
201
420
1520
1620
1720
1820
19
Sep-2
0
Num
bers
of C
hild
ren
and
Cou
ntri
es
Year
Countries
Children*
© 2020 The Progeria Research Foundation. All Rights Reserved. As of September 30 2020
Tracking Children with Progeria Through Prevalence
Ø How does PRF estimate how many children we are searching for,
and in what countries? We use population prevalence.
Ø Prevalence is the proportion of children with Progeria per total
population.
© 2020 The Progeria Research Foundation. All Rights Reserved. As of September 30, 2020
How Prevalence Is Estimated
Ø At PRF, we use a formula based on the number of children
we’ve identified in the US. We then expand that out to the
world population.
Ø We do this because we have the most complete reporting for
the US and since Progeria has no gender, ethnic, or other
biases, we assume that the prevalence in the US is the
same prevalence in other countries.
Ø PRF estimates prevalence for years when the official US
census provides a reliable population number.
© 2020 The Progeria Research Foundation. All Rights Reserved. As of September 30, 2020
USA Prevalence of Progeria
January, 2020 population statistics:
The US population was:
Number of PRF-identified children with HGPS in the US:
18Prevalence of HGPS in the US: 18 in 330 million is about
© 2020 The Progeria Research Foundation. All Rights Reserved. As of September 30, 2020
*estimates routinely fall between 1 in 18 - 1 in 20 million people.
Prevalence and World Population of Progeria
Given the world population as of September 30, 2020
.
© 2020 The Progeria Research Foundation. All Rights Reserved. As of September 30, 2020
Using Prevalence To Find Children In A Certain Country
We can now use the total population estimates for any given country, in order to
understand whether we have found most or all children in a particular country.
Ø For example, as of January, 2019:
Brazil’s population was estimated as
people
Using Prevalence, the number of children living
PRF has identified 7 of these 10 children, and is searching for the 3 others
with Progeria in Brazil is 212,392,717/20,000,000 = 10
* Data based on the latest United Nations Population Division estimates
© 2020 The Progeria Research Foundation. All Rights Reserved. As of September 30, 2020
International Progeria Registry*
© 2020 The Progeria Research Foundation. All Rights Reserved. As of September 30, 2020
Program Goals:
ØPatient identificationØOutreach to patient families and their physicians ØA springboard for program enrollment
Registry forms available athttps://www.progeriaresearch.org/international-registry-2/
*PRF International Registry includes those with genetically confirmed or clinically suspected Progeria, as well as those with other possible progeroid syndromes
315 Children Have Registered With PRF
36
© 2020 The Progeria Research Foundation. All Rights Reserved. As of September 30, 2020
5461
82
102
118129
151160
181193
208
224
241254
269
285
315
40
60
80
100
120
140
160
180
200
220
240
260
280
300
320
Num
ber o
fReg
istra
nts
20 2020
02001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 Sept
Year 2020
From 65 Countries and 1 TerritoryAlgeria Bulgaria Dominican Republic Guatemala Ireland Mexico Panama Russia Suriname USA
Argentina Canada Ecuador Honduras Israel Morocco Peru Saudi Arabia Sweden Venezuela
Australia Chile Egypt Hong Kong Italy Nepal Philippines Serbia Switzerland Vietnam
Bangladesh China England India Japan Netherlands Poland South Africa Tanzania
Belgium Colombia Finland Indonesia Kazahkstan Oman Portugal South Korea Togo
Bolivia Czech Republic France Iran Libya Pakistan Puerto Rico Spain Turkey
Brazil Denmark Germany Iraq Malaysia Palestine Romania Sri Lanka Ukraine
Children Around the World Registered with PRFAs of September 30 , 2020
© 2020 The Progeria Research Foundation. All Rights Reserved.
South America 15.2%
N=48
Europe15.6%
N=49
North America 26.3%
N=83
Asia 35.6%
N=112
Africa5.7%N=18
Australia 1.6%
N=5
…And All Continents
Participation (%) By Continent
© 2020 The Progeria Research Foundation. All Rights Reserved. As of September 30, 2020
Program Goal:
ØGenetic Sequence Testing for Progeria-causing mutations
Pre-requisites for Testing:
ØRegistration with PRF International Registry
ØOne or more of the following
Family history - proband, prenatal Phenotypic
presentation - proband, postnatal Relative of
positive proband
Testing information available at
https://www.progeriaresearch.org/the-prf-diagnostic-testing-program/
PRF Diagnostics Program
© 2020 The Progeria Research Foundation. All Rights Reserved. As of September 30, 2020
As of September 30, 2020:
Total Number of Proband Tests Performed:
Exon 11 (HGPS) Mutations:
Other Progeroid Laminopathies (Exons 1 – 12):
Zmpste24 Mutations :
Average Number of Patients Tested Per Year :
Diagnostics Testing Summary
All tests are performed in a Clinical Laboratory Improvement Amendments (CLIA) certified facility.
102
13
2
9
150
© 2020 The Progeria Research Foundation. All Rights Reserved.
Mutations Identified Through PRF Diagnostics Program
DNA Mutation Amino Acid Effect ZygosityProgerin
Producing?Number
Diagnosed
Classic HGPS – LMNA Mutation
1824 C>T, exon 11 G608G heterozygous Yes 89
Non Classic HGPS– LMNA Mutation
1822 G>A, exon 11 G608S heterozygous Yes 4
1821 G>A, exon 11 V607V heterozygous Yes 2
1868 C>G, exon 11 T623S heterozygous Yes 1
1968+5 G>C, intron 11 --------- heterozygous Yes 2
1968+1 G>C, intron 11 --------- heterozygous Yes 2
1968+2 T>A, intron 11 heterozygous Yes 1
1968+1 G>A, intron 11 heterozygous Yes 1
Progeroid Laminopathy– LMNA Mutation
1579 C>T, exon 9 A527C heterozygous No 1
1579 C>T, exon 9 A527C homozygous No 6
1580G>T, exon9 A527L Homozygous No 2
1619 T>C, exon 10 M540T homozygous No 3
331 G>A, exon 1 G111L heterozygous No 1
Progeroid Laminopathy– Zmpste24 Mutation
1274T>C, exon 10 L425P homozygous No 2
© 2020 The Progeria Research Foundation. All Rights Reserved. As of September 30, 2020
12 13 17 21 24 24 26 28 29 29 29 29 30 32 33 35 3530
3746
51 5662
71 76 82 87 94 97107 108
113 113
14 23
131
3543
54
6775
8088
99105
111116
123 127
139 141148 150
0
20
40
60
80
100
120
140
160
2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 Sept2020
Num
berT
este
d
Year
Total Testing LMNA Negative Total Testing LMNA Positive Total Clinically Affected Tested by PRF
© 2020 The Progeria Research Foundation. All Rights Reserved. As of September 30, 2020
*Graph does not include Parents/Siblings tested
Number of Affected Children/Adults Tested and the Number Testing Positive for LMNA Gene Mutation*
Longitudinal Testing Data for PRF Diagnostics Program
PRF Cell & Tissue Bank
Program Goals:
ØProvide a resource for researchers worldwide
ØEnsure the sufficient availability of genetic and biological materials essential for research aimed at understanding the pathophysiology of disease and the links between Progeria, aging and heart disease
ØObtain long-term clinical data
© 2020 The Progeria Research Foundation. All Rights Reserved. As of September 30, 2020
Resource information available at: https://www.progeriaresearch.org/cell-and-tissue-bank/
PRF Cell & Tissue Bank Holdings
73 Dermal Fibroblast Lines from affected and parents
124 Lymphoblast Lines from affected, parents and siblings
10 Induced Pluripotent Stem Cell Lines from affected and parents
As of September 30, 2020:
Total Number of Participants: 283*
6 Immortalized Fibroblast Cell Lines from affected and parents
* Participants may have donated multiple times© 2019 The Progeria Research Foundation. All Rights Reserved.
© 2020 The Progeria Research Foundation. All Rights Reserved. As of September 30, 2020
Number Of Cell Lines By Year
33 35 36 36 39 42 46
61 6578 78 78 79 82 86 88 88 88
17
20
29
4454
6269
7480
92100
112 116 116 118121
123 124 124 125
37
62
7990
98108
116126
153165
190 194 194 197203
209 212 212 213
0
50
100
150
200
250
Num
ber
of C
ellL
ines
Year
Total Cell Lines Parents/Siblings Cumulative Total Cell Lines Affected CumulativeTotal Number of Cell Lines
© 2020 The Progeria Research Foundation. All Rights Reserved. As of September 30, 2020
PRF Cell & Tissue Bank Distribution
Research Teams From Countries Have Received
As of September 17, 2020:
25194
Cell Lines
DNA Samples
Tissue, plasma, serum and other biological samples
Lonafarnib Samples
Senescent Progeria Fibroblasts in Culture
© 2020 The Progeria Research Foundation. All Rights Reserved.
Biological Sample Distribution Over Time
20 20 16
32
17 12
92
24 29 27
95
62
108
122
168178
135
219
58
0
50
100
150
200
250
2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020
Num
ber
of S
ampl
es D
istr
ibut
ed
Year
Fibroblast Lines Lymphoblast Lines iPSC Lines
DNA Immortalized Cell Lines # = Total Distributed
© 2019 The Progeria Research Foundation. All Rights Reserved.
USA Cell & Tissue Bank Recipients
As of September 30, 2020
Recipient Institution Recipient InstitutionMansoor Amiji Northeastern University Martin Dorf Harvard Medical SchoolAngelika Amon Massachusetts Institute of Technology Stephen Doxsey U. of Massachusetts Medical SchoolStelios Andreadis U. of Buffalo Jack Elias Brown University School of MedicineSamuel Beck MDI Biolab Mike Erdos National Institutes of HealthShelley Berger U of Pennsylvania Jed Fahey Johns Hopkins UniversityBruce Blazer U. of Minnesota Toren Finkel NIHJoseph Bonventre Brigham and Women’s Hospital Shridar Ganesan Cancer Institute of New JerseyDemetrios Braddock Yale University Abhimanyu Garg U. of Texas Southwestern Medical CenterJonathan Brown Vanderbilt University Glenn Gerhard Temple UniversityTed Brown Institute for Basic Research (IBR) David Gilbert Florida State UniversityMark Burkhard University of Wisconsin-Madison Thomas Glover U.of Michigan Medical SchoolJudy Campisi Buck Institute Robert Goldman Northwestern UniversityKan Cao U. of Maryland Susana Gonzalo St. Louis School of MedicineLi Chai Harvard University Lilian Grigorian Cedars Sinai Medical CenterFrancis Collins National Genome Research Institute Gregg Gundersen Columbia University Medical CenterLucio Comai U. of Southern California Curtis Harris National Institutes of HealthDaniel Conway Virginia Commonwealth University Martin Hetzer Salk InstituteJohn Cooke Houston Methodist Research Institute Liam Holt NYU Institute for Systems GeneticsMauro Costa-Mattioli Baylor College of Medicine Steve Horvath UCLA
Adrienne Cox U. of North Carolina at Chapel Hill Johnny Huard U. of Texas Health Science Center at HoustonGreg Crawford Duke University Medical Center Jay Humphrey Yale UniversityAntonei Csoka Howard University Kohta Ikegami The University of ChicagoKris Dahl Carnegie Mellon University Vishwanath Iyer U. of Texas AustinGeorge Daley Boston Children's Hospital Jose Jalife University of MichiganChanning Der U. of North Carolina at Chapel Hill David Kaplan Tufts UniversityMohanish Deshmukh U. of North Carolina at Chapel Hill Karen Katula UNC – GreenboroDennis Discher U. of Pennsylvania
© 2020 The Progeria Research Foundation. All Rights Reserved.
USA Cell & Tissue Bank RecipientsRecipient Institution Recipient Institution
Timothy Kowalik U. of Massachusetts Medical School Taihao Quan University of MichiganDmitri Krainc Massachusetts General Hospital Joseph Rabinowitz Temple UniversityJan Lammerding Harvard University Ana Robles National Cancer InstituteDudley Lamming U of Wisconsin-Madison David Sabatini Whitehead InstituteJeanne Lawrence U. of Massachusetts Medical School John Sedivy Brown UniversityJoan Lemire Tufts University School of Medicine Christian Sell Drexel University College of MedicineKam Leong Columbia University Jerry Shay UT Southwestern Medical CenterJason Lieb U. of North Carolina at Chapel Hill Jamila H Siamwala Brown UniversityDavid Liu Harvard University Andrew Sonis Boston Children's HospitalChengzu Long New York University School of Medicine Ronald St-Louis OVIBIO Corporation, Inc.Shigemi Matsuyama Case Western Reserve University Earl Stadtman National Heart, Lung & Blood InstituteRachel Patton McCord University of Tennessee Dylan Taatjes U. of ColoradoAndrew Mendelsohn Regenerative Sciences Institute Marc Tatar Brown University
Susan Michaelis Johns Hopkins University School of Medicine Rajarajan Amirthalingam Thandavarayan Houston Methodist Research Institute
Jeffrey Miner Washington University Eduardo Torres U. Of Massachusetts Medical SchoolTom Misteli National Cancer Institute George Truskey Duke UniversityAshby Morrison Stanford University Alan Waldman University of South CarolinaMarsha Moses Boston Children’s Hospital Steve Warren Emory University School of MedicineElizabeth Nabel National Heart, Lung & Blood Institute Howard Worman Columbia UniversityTimothy Osborne Sanford Burnham Medical Research Institute Tom Wight Hope Heart InstituteJunko Oshima U. of Washington Joseph Wu Stanford UniversityBryce Paschal U. of Virginia Feng Zhang The Broad InstituteHamel Patel U. Of California, San Diego Alessandra Zonari OneSkin TechnologiesMary Patti Joslin Diabetes Center You Zou East Tennessee University
© 2020 The Progeria Research Foundation. All Rights Reserved. As of September 30, 2020
International Cell & Tissue Bank Recipients
Recipient Institution Country Recipient Institution Country
Andrea Ablasser Global Health Institute Switzerland Christopher Eskiw Saskatchewan University Canada
Vicente Andrés GarciaCentro Nacional de InvestigacionesCardiovasculares
Spain Gerardo Ferbeyre Université de Montréal Canada
Samuel Benchimol York University Canada Lino FerreiraCenter for Neuroscience and Cell Biology (CNC)
Portugal
Martin Bergö Karolinska Institutet Sweden Marco Foiani Instituto FIRC di Oncologia Molecolare ItalyMartin
Enrico Bertini Ospedale Pediatrico Bambino Gesù Italy Alain Garnier Université Laval Canada
Michael Blank Bar Ilan University Israel Yosef Gruenbaum The Hebrew University of Jerusalem Israel
Antonio Campos de Carvalho
Federal University of Rio de Janeiro BrazilNady El Hajj Hamad bin Khalifa University Qatar
Ana Carrera Centro Nacional de Biotecnologia Spain Robert Hegele University of Western Ontario Canada
Gordon Chan University of Alberta Canada Andreas Hermann University of Dresden Germany
Mario D. CorderoINEBIR- Instituto par el estudio de la Biologia de la Reproduccion Human Spain
Corinne Hoesli McGill University Canada
Lynne Cox University of Oxford England Junho K Hur Kyung Hee UniversityRepublic of Korea
Thomas Dechat Medical University of Vienna Austria Anthony Hyman Max-Planck-Institute of Molecular Cell Biology and Genetics
Germany
Annachiara DeSandre-Giovannoli
Laboratoire de Génétique Moléculaire France Jan Korbel European Molecular Biology Laboratory Germany
Jerome Dejardon Institute of Human Genetics France Christian Kubisch Institute of Human Genetics Germany
Karima Djabali TU-Munich Germany Varun Kumar Uniklinikum Heidelberg Germany
Ma Dongrui Singapore General Hospital Singapore Kirsztian Kvell University of Pecs Hungary
J. El Molto Molecular World, Inc Canada Taejoon KwonUlsan National Institute of Science & Technology
Korea
Maria Eriksson Medicinsk Naringslara Sweden Chiara LanzuoloCNR Institute of Cellular Biology & Neurobiology
Italy
International Cell & Tissue Bank Recipients
Recipient Institution Country Recipient Institution Country
Caterina La Porta University of Milan Italy Luis Pereira de Almeida Center for Neuroscience and Cell Biology (CNC) Portugal
Delphine Larrieu University of Cambridge England Fiorella Piemonte Ospedale Pediatrico Bambino Gesù Italy
Lucia Latella National Research Council (CNR) Italy Neale Ridgway University of Halifax Canada
Giovanna Lattanzi ITOI-CNR Unit of Bologna Italy Claudia Ruebe Saarland University Germany
Jean-Marc Lemaitre Institute of Functional Genomics France Kanaga Sabapathy National Cancer Centre Singaport Singapore
Nicolas Levy Génétique Médicale et Développement France Isabella Saggio Sapienza University of Rome Italy
Baohua Liu Shenzhen University China Kanda Sangthongpitag Experimental Therapeutics Centre Singapore
Elsa Logarinho Instituto de Biologia Molecular e Celular Portugal Yasuhiro Shimoyima Shinshu University Japan
Jun Lu Northeast Normal University China Ok Sarah Shin Korea University Guro Hospital Korea
Frank Lyko German Cancer Research Institute Germany Sanjay Sinha University of Cambridge England
Thorston Marquart University of Münster Germany Michael Speicher Medical University of Graz AustriaFelipe Alonso Massó Rojas
National Institute of Cardiology Ignacio Chávez Mexico William Stanford University of Toronto Canada
Scott Maynard Danish Cancer Society Research Institute Denmark Michael Walter University of Münster Germany
Ohad Medalia University of Zurich Switzerland Herbert Waldman Max Planck Institute Germany
Denis Mottet University of Liège Belgium Miguel Weil Tel Aviv university Israel
Silvia Ortega-Gutiérrez Universidad de Complutense de Madrid Spain Jesús Vazquez Cobos Centro Nacional de Investigaciones Cardiovasculares Spain
Selma Osmanagic-MyersMax Perutz Labs, Medical Universityof Vienna Austria
Alex Zhavoronkov Federal Clinical Research Centre Russia
Bum-Joon Park Pusan national University South Korea Zhongjun Zhou University of Hong Kong China
PRF Medical & Research Database
© 2020 The Progeria Research Foundation. All Rights Reserved. As of September 30, 2020
Program Goals:
ØCollect the patient health records for living and deceased children with Progeria
ØObtain long-term clinical data
ØAbstract data for longitudinal and cross-sectional analyses
ØBetter understand the clinical disease process in Progeria and aging related diseases
ØDevelop treatment strategies and recommendations for health care professionals and families
Ø Project staff obtain the patient’s medical records and film studies from birth throughout the participant’s lifespan.
Ø Medical records include visits to: primary care physicians, specialty physicians, hospital emergency rooms, hospital admissions, dentists, physical therapy, occupational therapy and school health records.
Ø Retrospective data abstraction protocol allows for specifically targeted or broad spectrum of data.
© 2020 The Progeria Research Foundation. All Rights Reserved. As of September 30, 2020
How The PRF Medical & Research Database Works
Enrollment information available at: https://www.progeriaresearch.org/medical-database/
Medical & Research Database Participation
184 Participants are enrolled from countries and US territoryArgentina China Germany Italy Netherlands Puerto Rico Sri Lanka USAAustralia Columbia Guatemala Japan Oman Romania Suriname Venezuela
Bangladesh Denmark Honduras Kazakhstan Pakistan Russia Sweden VietnamBelgium Dominica Republic India Libya Peru Senegal Tanzania
Brazil England Indonesia Mexico Philippines South Africa TogoCanada Egypt Ireland Morocco Poland South Korea Turkey
Chile France Israel Nepal Portugal Spain Ukraine
As of September 30, 2020© 2020 The Progeria Research Foundation. All Rights Reserved.
Database Longitudinal Enrollment
11 11 13 16 17 22 27 27 31 34 35 36 39 41 42 43 47 48 51 5120 20
3143 48
5970
7785
99111
117126
132
147 152164
176183 184
200
180
160
140
120
100
80
60
40
20
0
Num
ber
of P
artic
ipan
ts a
ndC
ount
ries
2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 Sept2020
Year
Children Enrolled in The PRF Medical & Research Database and the Countries of Residence
Cumulative Number of Countries
© 2020 The Progeria Research Foundation. All Rights Reserved. As of September 30, 2020
Ø Participants with Medical Records Reports:
Types Of Data Collected
Ø Participants with Radiology Studies: 62
166
160°
© 2020 The Progeria Research Foundation. All Rights Reserved. As of September 30, 2020
PRF Weighing-In Program
Ø A sub-program of The PRF Medical & Research Database
Ø Collects weight-for-age data prospectively:
Home scale provided by PRF
Parents weigh child weekly or monthly
Report weights electronically
© 2020 The Progeria Research Foundation. All Rights Reserved.
Weighing-In Program Participation
Participants are enrolled from countries and US territory122Argentina China Germany Ireland Morocco Poland Senegal Tanzania
Australia Colombia Guatemala Israel Nepal Portugal South Africa Turkey
Bangladesh Denmark Honduras Italy Pakistan Puerto Rico South Korea Ukraine
Belgium Dominion Republic India Japan Peru Romania Spain USA
Brazil England Indonesia Mexico Philippines Russia Sri Lanka Venezuela
Canada Togo Vietnam
Weighing in Participants Around the World As of April 1, 2019
© 2020 The Progeria Research Foundation. All Rights Reserved.
Participants Enrolled In The PRF Weighing-In Program and Countries of Residence
20 24 26 29 30 31 34 37 39 42 43
4449
56
74 77 8088
99106
118 122
20
40
60
80
100
120
140N
umbe
r E
nrol
led
and
Num
ber
of
C
ount
ries
(Cum
ulat
ive)
02008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018
Year
Number of Countries
Number Enrolled
© 2020 The Progeria Research Foundation. All Rights Reserved. As of September 30, 2020
Ø Data from this program were key in the development of primary outcome measure for the first drug treatment trial for Progeria.
Ø As of December 1, 2018, children from The PRF Weighing-In Program have entered clinical treatment trials using this data.
Clinical Trials And The Weighing-In Program
Failure to Thrive Starts Towards End of Year One
PRF-Funded Clinical Treatment Trials
© 2020 The Progeria Research Foundation. All Rights Reserved. As of September 30, 2020
Clinical Drug Treatment Trials
Goals:
Ø To define the natural history of HGPS in quantifiable terms that will expand our ability to measure treatment outcome
Ø To assess the safety of new treatments for HGPS
Ø To measure effects of treatments for children with HGPS on disease status, changes in health, and survival
© 2020 The Progeria Research Foundation. All Rights Reserved. As of September 30, 2020
Current Therapeutic Intervention Strategies
Farnesyl-PP + Preprogerin 1
Preprogerin 2
Preprogerin 3
Progerin
Farnesyl transferase
Zmpste24
ICMT
AutophagyEverolimus
Key Properties ofPreprogerin/Progerin
not farnesylated; terminal CaaX box
farnesylated
farnesylated; terminal aaX cleaved
farnesylated; carboxymethylated
mTOR
Lonafarnib
© 2020 The Progeria Research Foundation. All Rights Reserved. As of September 30, 2020
Post-translational processing and medications currently under investigation in clinical treatment trials for Progeria. Items in green = enzymes. Items in red = clinical trial medications that inhibit corresponding enzymes. Lonafarnib is a farnesyltransferase inhibitor. Everolimus is a rapamycin analogue that inhibits mTOR and promotes cellular autophagy. FT=farnesyltransferase.
Year Drug(s) Phase Location # Countries
2007-2010 Lonafarnib 2 Boston 28 17
2009Lonafarnib
PravastatinZoledronate
Feasibility Boston 5 1
2009-2013
Lonafarnib Pravastatin Zoledronate
2 Boston 45 24
2014-present Lonafarnib 2 Boston 72 35
2016 –present
Lonafarnib Everolimus 1/2 Boston 63 27
2018 -present Lonafarnib Boston
39 from 23 countries enrolled to date
PRF Funds Clinical Treatment Trials
Participation in PRF Clinical Trials
96 Children have participated in PRF Clinical Trials from countries:
Argentina China England Italy Pakistan Romania Sri Lanka Ukraine
Australia Colombia Germany Japan Peru Russia Sweden USA
Belgium Denmark Honduras Libya Philippines South Africa Tanzania Venezuela
Brazil Dominican Republic India Mexico Poland South Korea Togo
Canada Egypt Israel Morocco Portugal Spain Turkey
Trial Participants Around theWorld As of September 30, 2020
© 2020 The Progeria Research Foundation. All Rights Reserved.
Treatment Trial Collaborations For Success
Ø The children are seen by physicians from:Boston Children’s Hospital
Dana-Farber Cancer Institute
Brigham and Women’s Hospital
Ø Data were also generated by scientists from:Alpert Medical School at Brown University
Brown University School of Public Health
University of California Los Angeles
National Human Genome Research Institute
Schering-Plough Research Institute
Ø Lonafarnib generously provided by EigerØ Everolimus generously provided by Novartis
© 2020 The Progeria Research Foundation. All Rights Reserved. As of September 30, 2020
Clinical Treatment Trial Efficacy Results
Lonafarnib, a type of farnesyltransferase inhibitor (FTI) is our first treatment for Progeria.
Ø Results showed improvement in:
Rate of weight gain
Increased vascular distensibility
Improved bone structure
Better neurosensory hearing
Increased Lifespan
Gordon et al, PNAS, 2011
© 2020 The Progeria Research Foundation. All Rights Reserved. As of September 30, 2020
Clinical Trial PublicationsDrug Effect:
Association of Lonafarnib Treatment vs No Treatment With Mortality Rate in Patients With Hutchinson-Gilford Progeria Syndrome. Gordon et al, JAMA, 2018, 319(16):1687-1695.
Survey of Plasma Proteins in Children with Progeria Pre-therapy and On-Therapy with Lonafarnib. Gordon et al, Pediatric Research, 2018 Jan 17. Epub Ahead of Print.
Clinical Trial of the Protein Farnesylation Inhibitors Lonafarnib, Pravastatin, and Zoledronic Acid in Children With Hutchinson-Gilford Progeria Syndrome. Gordon et al, Circulation, 2016 Jul 12;134(2):114-25.
Seeking a Cure for One of the Rarest Diseases: Progeria. Collins FS. Circulation, 2016 Jul12;134(2):126-9.
Impact of Farnesylation Inhibitors on Survival in Hutchinson-Gilford Progeria Syndrome. Gordon et al, Circulation, 2014 Jul 1;130(1):27-34.
Moving from Gene Discovery to Clinical Trials in Hutchinson-Gilford Progeria Syndrome. King et al, Neurology, 2013 Jul 30;81(5):408-9.
Clinical Trial of a Farnesyltransferase Inhibitor in Children with Hutchinson-Gilford Progeria Syndrome. Gordon et al, Proceedings of the National Academy of Sciences, 2012 Sep 24.
Neurologic Features of Hutchinson-Gilford Progeria Syndrome after Lonafarnib Treatment. Ullrich et al, Neurology, 2013, 81:427-430.
General:
Phenotype and Course of Hutchinson-Gilford Progeria Syndrome. Meredith et al, New England Journal of Medicine, 2008, 358(6): 592-604.
Pubertal Progression in Adolescent Females with Progeria. Greer et al, Journal of Pediatric and Adolescent Gynecology, 2017 Dec 17. Epub Ahead of Print.
Dermatology:
Initial Cutaneous Manifestations of Hutchinson-Gilford Progeria Syndrome. Rork et al, Pediatric Dermatology,2014,1-7.
© 2020 The Progeria Research Foundation. All Rights Reserved. As of September 30, 2020
Clinical Trial Publications ContinuedDental:
Hutchinson-Gilford Progeria Syndrome: Oral and Craniofacial Phenotypes. Domingo et al, Oral Diseases, 2009, 15(3):187-195.
Cerebrovascular:
Imaging Characteristics of Cerebrovascular Arteriopathy and Stroke in Hutchinson-Gilford Progeria Syndrome. Silvera et al, American Journal of Neuroradiology, 2013 May;34(5):1091-7.
Cardiology:Cardiac Abnormalities in Patients With Hutchinson-Gilford Progeria Syndrome. Prakask, et al, JAMA Cardiology, 2018, Apr 17;115(16):4206-4211.
Mechanisms of Premature Vascular Aging in Children with Hutchinson-Gilford Progeria Syndrome. Gerhard-Herman M, et al., Hypertension. 2012Jan;59(1):92-97; Epub 2011 Nov 14.
Skeletal: Hutchinson-Gilford progeria is a skeletal dysplasia. Gordon,et al., Journal of Bone and Mineral Research. 2011Jul;26(7):1670-9.
A Prospective Study of Radiographic Manifestations in Hutchinson-Gilford Progeria Syndrome. Cleveland et al, Pediatric Radiology, 2012 Sep;42(9):1089-98. Epub 2012 Jul 1.
Craniofacial Abnormalities in Hutchinson-Gilford Progeria Syndrome. Ullrich et al, American Journal of Neuroradiology. 2012 Sep;33(8):1512-8.
Extraskeletal Calcifications in Hutchinson-Gilford Progeria Syndrome. Gordon, CM et al. Bone. 2019 Aug;125:103-111. Epub 2019 May 8.
. Skeletal maturation and long-bone growth patterns of patients with Progeria: a retrospective study. Tsai, A et al,The Lancet. Child and Adolescent Health. 2020. ePub 2020 Feb 28.
Ophthalmology:Ophthalmologic Features of Progeria. Mantagos et al., American Journal of Ophthalmology, 2017 Jul 27.
Audiology:Otologic and Audiologic Manifestations of Hutchinson-Gilford Progeria Syndrome. Guardiani et al, The Laryngscope, 2011, 121(10): 2250-2255.
Microbiome at Sites of Gingival Recession in Children with Hutchinson-Gilford Progeria Syndrome. Bassir et al.Journal of Periodontology. 2018, 89(6): 635-644.
© 2020 The Progeria Research Foundation. All Rights Reserved. As of September 30, 2020
Program Goals:
Ø Attract high level researchers to the field of Progeria, andprovide the ability for them to thrive in the field
Ø Foster researchers of interest to PRF’s mission
Ø Encourage high quality publications
Ø Stimulate novel research that will lead to larger grants from other resources such as NIH, Ellison Foundation, and others
Ø Projects that are likely to lead to clinical treatment trials within 5 years
Ø Development of gene and cell based therapies to treat Progeria
Grants program information available at https://www.progeriaresearch.org/research-funding-opportunities/
© 2020 The Progeria Research Foundation. All Rights Reserved. As of September 30, 2020
PRF Grants Program
Back Row (L to R): Tom Glover PhD, Vicente Andrés Garcia PhD, Tom Mistelli PhD, Maria Eriksson PhD, W Ted Brown MD, PhD, Frank Rothman PhD (emeritus), Bryan Toole PhD(chair)
Front Row (L to R): Monica Kleinman MD, Christine Harling-Berg PhD, Judy Campisi PhD, Leslie Gordon MD, PhD, Marsha Moses PhD
PRF Medical Research CommitteeVolunteer MRC Reviews Grant Applications Semi-annually
© 2020 The Progeria Research Foundation. All Rights Reserved. As of September 30, 2020
PRF Granting Structure
© 2020 The Progeria Research Foundation. All Rights Reserved. As of September 30, 2020
PRF’s research focus is highly translational. Topics must fall within the following research priorities:
Ø Projects that are likely to lead to clinical treatment trials within 5 years. This includes the discovery and/or testing of candidate treatment compounds in cell-based or animal models of HGPS. Only proposals that test compounds in a progerin-producing animal or cell model will normally be considered. Analyses in non progerin-producing models are acceptable, but only as a comparison to progerin-producing models and with strong justification.
Ø Development of gene-and cell-based therapies to treat Progeria
Ø Assessment of natural history of disease that may be important to developing outcome measures in treatment trials (preclinical or clinical)
Phase I Proposals: Awards are typically for 1-2 years in the range of $75,000/year. PRF will conduct a thorough cost analysis for each project during evaluationsof submissions.
Required Qualifications. Principal investigators must hold a faculty appointment or equivalent. Awards will be granted only to applicants affiliated with institutions with 501(c)3 tax-exempt status, or the equivalent for foreign institutions.
Letter of Intent (LOI). A letter of intent is required and must be approved before a full applicationwill be considered. Instructions to submit a Letter of Intent and grant application information, canbe found at https://www.progeriaresearch.org/grant-application/.
As of September 30, 2020, The PRF funding rate is 31%
fundedØ Since inception, grant applications received and Ø PRF has funded principal investigators from institutions
in countries
Lamina A, progerin, Lamin B in HGPS and aging
Genetics and nuclear function
Preclinical Drug Therapy
Molecular Abnormalities and Therapies
Vascular Pathology
Mouse Models
Stem Cell Investigations and Therapy
Clinical Trials
Grant Funding Rates And Topics
© 2020 The Progeria Research Foundation. All Rights Reserved. * Submissions include Letters of Intent and Full Grants
USA PRF GranteesGRANTEE NAME INSTITUTION GRANTEE NAME INSTITUTION
Richard Assoian University of Pennsylvania Joan Lemire Tufts University of Medicine
Jemima Barrowman Johns Hopkins University Jason Lieb University of North Carolina
Juan Carlos Belmonte Salk Institute for Biological Studies Monica Mallampalli The Johns Hopkins School of Medicine
Ted Brown The Institute for Basic Research in Developmental Disabilities
Susan Michaelis The Johns Hopkins School of Medicine
Abigail Buchwalter University of California, San Francisco Thomas Misteli National Cancer Institute
Kan Cao NIH; University of Maryland Marsha Moses Harvard Medical School; Boston Children’s Hospital
Christopher Carroll Yale University Junko Oshima University of Washington
Francis Collins National Institute of Health Bryce Paschal University of Virginia
Lucio Comai University of Southern California Joseph Rabinowitz Temple Medical School
John P. Cooke Houston Methodist Research Institute John M. Sedivy Brown University
Kris Dahl Carnegie Mellon University Dale Shumaker Northwestern University
Jed W. Fahey Johns Hopkins School of Medicine Michael Sinensky East Tennessee State University
Toren Finkel NIH Brian Snyder Beth Israel Hospital
Loren Fong UCLA Dylan Taatjes University of Colorado
Michael Gimbrone Brigham & Women's Hospital Jakub Tolar University of Minnesota
Thomas W. Glover University of Michigan Katherine Ullman University of Utah
Robert Goldman Northwestern University Thomas Wight Benaroya Research Institute
Leslie B. Gordon Tufts University School of Medicine; Brown U. Katherine Wilson Johns Hopkins University
John Graziotto Massachusetts General Hospital Stephen Young UCLA
Brian Kennedy Buck Institute for Research on Aging Yue Zou East Tennessee State University
Jan Lammerding Cornell University
Dudley Lamming University of Wisconsin Madison
© 2020 The Progeria Research Foundation. All Rights Reserved. As of September 30, 2020
International PRF Grantees
GRANTEE NAME INSTITUTION COUNTRYVicente Andrés Garcia Centro Nacional de Investigaciones Cardiovasculares SpainSamuel Benchimol York University, Toronto CanadaMartin Bergö Karolinska Institute SwedenClaudia Cavadas University of Coimbra PortugalJesús Vázquez Cobos Centro Nacional de Investigaciones Cardiovasculares SpainThomas Dechat Medical University of Vienna AustriaKarima Djabali Technical University of Munich GermanyMaria Eriksson Karolinska Institute SwedenGerardo Ferbeyre Université de Montreal CanadaCélia Ferreira de OliveiraAveleira University of Coimbra PortugalRoland Foisner Medical University of Vienna AustriaGiovanna Lattanzi University of Bologna ItalyElsa Logarinho University of Porto PortugalEvgeny Makarov Brunel University EnglandSilvia Ortega-Gutiérrez Universidad Complutense de Madrid SpainBum-Joon Park Pusan National University KoreaIsabella Saggio Sapienza University of Rome ItalyCharlotte Sorenson Centro Nacional de Investigaciones Cardiovasculares SpainWilliam Stanford University of Toronto CanadaColin Stewart Institute of Medical Biology SingaporeRicardo Villa-Bellosta Instituto de Investigación Sanitaria - Fundación Jiménez Díaz SpainAnthony Weiss University of Sydney AustraliaZhongjun Zhou University of Hong Kong China
© 2020 The Progeria Research Foundation. All Rights Reserved. As of September 30, 2020
Meeting Goals:
ØTo promote collaboration between basic and clinical scientists toward progress in Progeria, cardiovascular, and aging research
PRF has held international scientific meetings
PRF Scientific Meetings
12
© 2020 The Progeria Research Foundation. All Rights Reserved.
2018 PRF Workshop
As of September 30, 2020
These are large multi-day workshops open to all scientists. Clinical and basic researchers spend intense days sharing data and planning new collaborations for progress towards treatments and cure.
Various NIH Institutes have funded all international workshops through R13and other granting mechanisms
Other organizations have also generously sponsored workshops
International Workshops Promoting Global Interest In Progeria, Cardiovascular Disease And Aging
© 2020 The Progeria Research Foundation. All Rights Reserved.
Growth of Global Interest In PRF Workshops
5646
52
3 5 2010 30 10
3610
18 14 14
4656
90100
140
180173
156
180
160
140
120
100
80
60
40
20
02001 2003 2005 2013 2016 2018
Num
ber
2007 2010PRF Workshop Year
Number of Posters
Registrant Countries
Registrant Number
© 2020 The Progeria Research Foundation. All Rights Reserved. As of September 30, 2020
Subspecialty Scientific Meetings
Small, focused meetings designed to promote and support work in areas of high interest for Progeria
First Genetics Consortium Meeting – “Searchingfor the Progeria Gene”, August 23, 2002, BrownUniversity, Providence, RI
Second Genetics Consortium Meeting – “Post-gene Discovery”, July 30, 2003, Bethesda, MD
Bone Marrow Transplant Meeting – “Forging Ahead by Exploring Potential Treatments”, April 25-26, 2004, National Institutes of Health, Bethesda, MD
New Frontiers in Progeria Research (2012), Boston, MA
© 2020 The Progeria Research Foundation. All Rights Reserved. As of September 30, 2020
As of September 30, 2020:
Scientific articles have been published citing The Progeria Research Foundation Grants Funding Program
Scientific articles have been published citing PRF Cell & Tissue Bank resources:
➢
Publication list at www.progeriaresearch.org/prf-cell-and-tissue-bank-publications/
Scientific articles have been published citing The PRF Medical & Research Database:
Publication list at www.progeriaresearch.org/medical-database/
Scientific articles have been published from clinical trial data
See slide #54 and #55
Scientific Publications
32
© 2020 The Progeria Research Foundation. All Rights Reserved.
90
23
154
Progeria Clinical Care Handbook
722
The Progeria Handbook 2nd Edition. A Guide for Families & Health Care Providers of Children with Progeria. The Progeria Research Foundation. Leslie B. Gordon MD, PhD; Medical Director (editor) 2019.
Provided in English, Spanish and Japanese
Expert contributors from BostonChildren’s Hospital
Number of Progeria Care Handbooks distributed to families of those with Progeria and their care givers:
© 2020 The Progeria Research Foundation. All Rights Reserved. As of September 30, 2020
The Progeria Research Foundation
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Studying…Treating…
CURING
Together We WILL Find The Cure!www.progeriaresearch.org
© 2020 The Progeria Research Foundation. All Rights Reserved.