INFRAFRONTIER / IMPC Stakeholder Meeting 2018
Advancing Rare Disease Research and Gene Therapy Applications with Animal Models
Munich, Hilton Park Hotel, December 3-4, 2018
The second Stakeholder Meeting of INFRAFRONTIER, the European Research Infrastructure for phenotyping and archiving of model mammalian genomes, will be jointly organized with the International Mouse Phenotyping Consortium (IMPC). Thematic focus of the meeting is on advancing Rare Disease research and gene therapy applications with animal models.
The Stakeholder Meeting provides an excellent opportunity to support a better alignment of INFRAFRONTIER / IMPC platforms with current Rare Disease research and personalised medicine initiatives, and supports interactions with human genetics centers and clinical consortia. New partnerships can support the rapid impact of mouse functional genomics analyses on the understanding of human genetic variation and disease, and the translation into diagnostic and therapeutic approaches.
The Stakeholder Meeting will be structured into three main parts:
- Advancing Rare Disease research with animal models
- Gene therapy applications using animal models
- Young Investigator / Stakeholder presentations
Meeting aims are to:
- Raise awareness of INFRAFRONTIER / IMPC platforms among the rare disease community
- Present collaborative mechanisms advancing rare disease research with model organisms
- Present use cases for the utility of model organisms to advance rare disease research
- Present advances in the preclinical testing of gene therapy approaches to cure human diseases.
- Strengthen interactions with rare disease and clinical research consortia
Monday, December 3:
- Model organisms facilitate rare disease diagnosis and therapeutic research
- EU collaborative and national initiatives targeting rare diseases
- Panel discussion: Advancing rare disease diagnosis and therapeutic research with model organisms - building bridges between basic and clinical research
- Young investigator / stakeholder presentations
- Policy perspective on sustainability of Research Infrastructures
Tuesday, December 4:
- Animal models for human gene therapy applications
- Gene editing in gene therapy of human (rare) diseases
- Optimising gene editing for therapeutics
- Gene editing for advanced therapies - Ethics, governance, and society
- Young investigator / stakeholder presentations
Scope and context
Despite recent successes in identifying causative mutations for human heritable diseases using sequencing technologies, an associated gene has not been identified for approximately half of the reported diseases. Discovery of the genotype-phenotype relationships is a critical step towards understanding of the mechanism of these diseases and the development of new treatments.
To address this challenge and to advance the functional analysis of human genetic variation, the International Mouse Phenotyping Consortium (IMPC) is creating a genome- and phenome-wide catalogue of gene function by characterizing new knockout-mouse strains across diverse biological systems through a broad set of standardized phenotyping tests.
Rare disease, clinical genetics and personalised medicine initiatives will benefit greatly from this emerging data and biological resources, which can be used to detect novel genotype-to-phenotype associations in diseases. The continued development of data analyses and integration approaches will be required to translate mouse functional genomics studies to a better understanding of human biology and disease. Furthermore, new genome-editing technologies such as CRISPR/Cas9 now enable the efficient derivation of precision disease models incorporating patient-specific genetic variants as a means of recapitulating essential aspects of human disease in mouse and other model organisms.
INFRAFRONTIER and IMPC offer unique platforms for the functional validation of genetic variants identified in exome/whole-genome sequencing approaches and the development of mouse models with predictive utility for efficient translation. Generation of precision animal models is key for understanding the pathogenesis of human genetic diseases, and the development of new therapies for rare diseases. INFRAFRONTIER partners supported numerous custom model development projects to investigate gene function and pathophysiology of rare diseases. The IMPC phenotyping discovery resource provides an unprecedented volume of high quality data, supporting clinicians to find relevant mouse models of human disease by orthologous gene and by shared phenotypic features.
Animal models also play an essential role for the development and preclinical testing of gene therapy approaches to cure human diseases. Animal models mimicking human disease conditions are essential at the preclinical stage before embarking on a clinical trial in the assessment of variables related to the use of viral vectors such as safety, efficacy, dosage and localization of transgene expression. Choosing a suitable disease-specific model is of paramount importance for successful clinical translation.
Gene editing is the next frontier in gene therapy and promises to correct genetic mutations that may cause disease, and to create and control genetic information within patient cells. Thousands of incurable genetic diseases are now theoretically treatable by gene editing approaches. In this context, animal models are essential tools for testing gene editing reagents and delivery systems.
The Stakeholder Meeting provides an excellent opportunity to explore a better alignment of INFRAFRONTIER / IMPC platforms with current rare disease and personalised medicine initiatives, and supports interactions with human genetics centers, clinical consortia and biobanks. Effective collaborative mechanisms connecting gene discovery projects with model organism communities such as the Canadian Rare Diseases Models and Mechanisms Network will be presented at the Stakeholder Meeting. New emerging partnerships will support the rapid impact of mouse functional genomics analyses on the understanding of human genetic variation and disease, and the translation into diagnostic and therapeutic approaches.
- Meehan et al., (2017) Disease model discovery from 3,328 gene knockouts by The International Mouse Phenotyping Consortium. Nature Genetics
- Wangler et al., (2017) Model organisms facilitate Rare Disease diagnosis and therapeutic research. Genetics
Confirmed speakers are:
- Martin Biel, Ludwig-Maximilians-Universität München (LMU), GE
- Fatima Bosch, Autonomous University of Barcelona (UAB), ES
- Steve Brown, MRC Harwell, UK; IMPC Scientific Chair
- Philippe Campeau, University of Montreal, CAN
- Jacob Corn, ETH Zurich, CH
- Colin Fletcher, National Institutes of Health (NIH-NHGRI), USA
- Xue Gao, Rice University, USA
- Pietro Genovese, San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IT
- Melissa Haendel, Oregon Health & Science University, US
- Yann Herault, PHENOMIN-ICS, FR
- Martin Hrabě de Angelis, Helmholtz Zentrum München, Institute of Experimental Genetics & INFRAFRONTIER GmbH, GE
- Jan Hrusak, Czech Academy of Sciences, J. Heyrovsky Institute of Physical Chemistry, CZ
- Daria Julkowska, French National Research Agency (ANR), FR
- Monica Justice, University of Toronto, SickKids Research Institute, CAN
- Paul Lasko, McGill University, CAN
- Fabio Mammano, CNR-Institute of Cell Biology and Neurobiology, IT
- Michal Minczuk, University of Cambridge, UK
- Federico Mingozzi, Genethon, Spark Therapeutics, FR/USA
- Lluis Montoliu, CSIC-CNB, ES
- Anna Need, GenomicsEngland, Queen Mary University of London, UK
- Holger Prokisch, Helmholtz Zentrum München, Institute of Human Genetics, GE
- Helene Puccio, Institute of Genetics and Molecular and Cellular Biology (IGBMC), FR
- Olaf Riess, University of Tübingen, Institute of Medical Genetics, GE
- Paula Rio, CIEMAT/CIBERER-ISCIII, ES
- Juliane Winkelmann, Helmholtz Zentrum München, Institute of Neurogenomics, GE
- Wolfgang Wurst, Helmholtz Zentrum München, Institute of Developmental Genetics, GE
- Shinya Yamamoto, Baylor College of Medicine, USA
Status: September 17, 2018
Monday, December 3:
08:00 - 08:45
Registration in the foyer of the Hotel Park Hilton, Munich
08:45 - 09:00
Welcome / setting the stage
Martin Hrabě de Angelis, Helmholtz Zentrum München & INFRAFRONTIER GmbH
INFRAFRONTIER Research Infrastructure
09:00 - 13:00
Session 1: Model organisms facilitate rare disease diagnosis and therapeutic research
Chairs: Martin Hrabě de Angelis, Colin McKerlie
Shinya Yamamoto, Baylor College of Medicine, Undiagnosed Disease Network / Model Organism Screening Center (MOSC): Model organisms facilitate rare disease diagnosis and therapeutic research
Yann Herault, PHENOMIN-ICS: PHENOMIN and the connection with the rare disease community
Lluis Montoliu, CSIC-CNB: New CRISPR derived animal models of albinism
Fabio Mammano, CNR-IBCN: In vivo genetic manipulation of inner ear connexin expression by bovine adeno-associated viral vectors
10:40 - 11.20 Coffee break in the foyer
Monica Justice, University of Toronto, SickKids Research Institute: A forward genetic suppressor screen in Mecp2 mice reveals therapies for Rett Syndrome
Juliane Winkelmann, Helmholtz Zentrum München: Dystonia – a heterogeneous rare neurological disease
Holger Prokisch, Helmholtz Zentrum München: Understand genetic variations in rare disorders leading to mitochondria-related disease
Steve Brown, MRC Harwell, IMPC Scientific Chair: The IMPC and Rare Diseases - A comprehensive catalogue of gene function for the mouse genome
Melissa Haendel, Oregon Health & Science University: Monarch Initiative - Facilitate identification of animal models of human disease through phenotypic similarity
13:00 - 14:00 Lunch break in the foyer
14:00 - 15:20
Session 2: EU collaborative and national initiatives targeting rare diseases
Chair: Yann Hérault
Olaf Riess, University of Tübingen, Institute of Medical Genetics: Solve-RD – solving the unsolved rare diseases
Daria Julkowska, French National Research Agency (ANR): European Joint Programme on Rare Diseases
Anna Need, Genomics England: Genomics England´s Rare Disease programme and GEMM initiative
Philippe Campeau, University of Montreal: The Canadian Rare Diseases Models and Mechanisms (RDMM) Network
15:20 - 16:05
Chair: Paul Lasko
Advancing rare disease diagnosis and therapeutic research with model organisms - building bridges between basic and clinical research
- Shinya Yamamoto, Baylor College of Medicine, Undiagnosed Disease Network (UDN)
- Steve Brown, MRC Harwell, International Mouse Phenotyping Consortium (IMPC)
- Olaf Riess, University of Tübingen, Solve-RD
- Philippe Campeau, University of Montreal, Rare Diseases Models and Mechanisms Network (RDMM)
16:05 - 16:50 Coffee break in the foyer
16:50 - 17:40
Session 3: Stakeholder presentations
Chair: Radislav Sedlacek
Speakers selected from submitted abstracts:
Vasanta Subramanian, University of Bath: Mice with a targeted deletion in the basal body protein Talpid3 (KIAA0586) exhibit cerebellar defects and ataxia reminiscent of Joubert syndrome.
Genay Pilarowski, John Hopkins University, School of Medicine: Haploinsufficiency of a histone modifier, Kmt2d, in a mouse model of Kabuki syndrome leads to defects in the B cell lineage and gut mucosal immunology.
Douglas Strathdee, Cancer Research UK, Beatson Institute: Altered cardiac cardiolipin levels In Barth Syndrome induce a stress response resulting in systemic metabolic changes.
Salla Kangas, University of Oulu: Creation of a knock-in mouse model for FINCA disease using the CRISPR/Cas9 technique.
17:40 - 18:00
Policy perspectives on European Research Infrastructures
Jan Hrusak, Czech Academy of Sciences, J. Heyrovsky Institute of Physical Chemistry, European Strategy Forum on Research Infrastructures (ESFRI): Long-term sustainability of Research Infrastructures
18:00 - 19:00
Drinks reception in the foyer
Tuesday, December 4: Agenda
08:30 - 10:10
Session 4: Animal models for human gene therapy applications
Chair: Fatima Bosch
Federico Mingozzi, GENETHON: Gene therapy treatment for a rare liver disease, Crigler-Najjar Syndrome
Helene Puccio, Institute of Genetics and Molecular and Cellular Biology (IGBMC): Gene therapy for Friedreich ataxia-associated cardiomyopathy
Martin Biel, Ludwig-Maximilians-Universität München (LMU): Genetic mouse models to develop gene therapies for retinal diseases
Fatima Bosch, Autonomous University of Barcelona (UAB): Disease correction by AAV-mediated gene therapy in mouse models of mucopolysaccharidosis
10:10 - 10:40 Coffee break in the foyer
10:40 - 12:00
Session 5: Gene editing in gene therapy of human (rare) diseases
Pietro Genovese, San Raffaele Telethon Institute for Gene Therapy (SR-TIGET): Preclinical modelling highlights the therapeutic potential of targeted gene correction in hematopoietic stem/progenitor cells and T cells for the treatment of primary immunodeficiencies
Paula Rio, CIEMAT/CIBERER-ISCIII: Therapeutic gene editing in CD34+ hematopoietic progenitors from Fanconi anemia patients
Michal Minczuk, University of Cambridge: Genome editing in mitochondria corrects a pathogenic mtDNA mutation in vivo
Xue Gao, Rice University: Treatment of autosomal dominant hearing loss by in vivo delivery of genome editing agents
12:00 - 13:00 Lunch break in the foyer
13:00 - 14:00
Session 6: Optimising gene editing for therapeutics
Chair: Wolfgang Wurst
Wolfgang Wurst, Helmholtz Zentrum München: CRISPR based approaches for gene therapy taking advantage of split Cas/intein syste
Jacob Corn, ETH Zürich: CRISPR/Cas9 genome editing: from mechanism to therapy
Colin Fletcher, NIH-NHGRI, Somatic Cell Genome Editing (SCGE) program: Animal models for gene editing research and preclinical testing
14:00 - 14:20
Gene editing for advanced therapies – ethics, governance, and society
Lluis Montoliu, CSIC-CNB: ARRIGE - Association for Responsible Research and Innovation in Genome Editing
14:20 - 15:20
Session 7: Stakeholder presentations
Chair: Lluis Montoliu
Speakers selected from submitted abstracts:
Beatriz Dorado, Centro Nacional de Investigaciones Cardiovasculares Carlos III: Generation and characterisation of a knockin LMNA c.1824C>T pig model of Hutchinson-Gilford progeria syndrome.
Davide Seruggia, Boston Children’s Hospital, Harvard Medical School: Uncoupling cellular fitness and fetal hemoglobin repression by targeting CHD4 CHDCT2 domain.
Belen Molla, Institute of Biomedicine of Valencia (IBV), CSIC: Preclinical study of novel pharmacological treatments in a mouse model of Lafora disease (Epm2b-/-).
Francesca Fallarino, University of Perugia: Endogenous tryptophan derivatives prevent the development of anti-FVIII antibodies in a hemophilia A mouse model.
Jukka Kallijärvi, University of Helsinki: Alternative oxidase-mediated respiration prevents lethal mitochondrial cardiomyopathy.
15:20 - 15:30
Meeting wrap up and closing
Martin Hrabě de Angelis
Hilton Hotel Munich Park
Situated on the edge of Munich's famous public park `Englischer Garten´, Hilton Munich Park is a modern, elegant International Business Hotel with all the amenities you may expect.
The hotel is only a 30 minutes drive away from Munich airport and within easy reach of all of the city's major businesses and attractions.
Am Tucherpark 7
D - 80538 Munich, Germany
INFRAFRONTIER is the European Research Infrastructure for phenotyping and archiving of model mammalian genomes. The INFRAFRONTIER Research Infrastructure provides access to first-class tools and data for biomedical research, and thereby contributes to improving the understanding of gene function in human health and disease using the mouse model. The core services of INFRAFRONTIER comprise the systemic phenotyping of mouse mutants in the participating mouse clinics, and the archiving and distribution of mouse mutant lines by the European Mouse Mutant Archive (EMMA).
In addition, INFRAFRONTIER provides specialised services such as the generation of germ-free mice, and training in state of the art cryopreservation and phenotyping technologies.
International Mouse Phenotyping Consortium (IMPC)
The IMPC addresses one of the grand challenges for biology and biomedical science in the 21st century – to determine the function of all the genes in the human genome and their role in disease. The goal of the IMPC is to develop a comprehensive catalogue of mammalian gene function. The IMPC aims to generate a null mutation for every protein-coding gene in the mouse genome, to acquire broad-based phenotype data for each mutation, and to disseminate the mutant resource and phenotype data to the scientific community.
Ultimately, the IMPC program will provide information on the function of all genes and genetic networks and a powerful dataset that will underpin fundamental new insights into the genetic bases for disease.
Financial support is provided by the INFRAFRONTIER2020 and IPAD-MD projects
INFRAFRONTIER2020 receives funding from European Union's Horizon 2020 research and innovation program under Grant Agreement number 730879
IPAD-MD receives funding from European Union's Horizon 2020 research and innovation program under Grant Agreement number 653961