prf by thenumbers · 2020. 11. 5. · prf by the numbers…here’s how it works Øwe take raw data...

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.


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.


http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-032.html

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

[email protected]


mailto:[email protected]

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


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


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


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


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


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.


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.


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


*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

.


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


International Progeria Registry*


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

https://www.progeriaresearch.org/international-registry-2/

315 Children Have Registered With PRF

36


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


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


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


https://www.progeriaresearch.org/the-prf-diagnostic-testing-program/


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


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


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


*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


Resource information available at: https://www.progeriaresearch.org/cell-and-tissue-bank/

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


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.

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


PRF Cell & Tissue Bank Distribution

Research Teams From Countries Have Received


25194

Cell Lines

DNA Samples

Tissue, plasma, serum and other biological samples

Lonafarnib Samples

Senescent Progeria Fibroblasts in Culture


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


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


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


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


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.


How The PRF Medical & Research Database Works

Enrollment information available at: https://www.progeriaresearch.org/medical-database/

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


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


Ø Participants with Medical Records Reports:

Types Of Data Collected

Ø Participants with Radiology Studies: 62

166

160°


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


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


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


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


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


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


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


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


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


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.


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.


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/


PRF Grants Program

https://www.progeriaresearch.org/research-funding-opportunities/

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


PRF Granting Structure


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/.

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


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


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


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


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


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



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


90

23

154

http://www.progeriaresearch.org/prf-cell-and-tissue-bank-publications/

http://www.progeriaresearch.org/prf-cell-and-tissue-bank-publications/

http://www.progeriaresearch.org/medical-database/

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:


The Progeria Research Foundation

Finding…Diagnosing…

Studying…Treating…

CURING

Together We WILL Find The Cure!www.progeriaresearch.org


http://www.progeriaresearch.org/

prf by thenumbers · 2020. 11. 5. · prf by the numbers…here’s how it works Øwe take raw data...

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