Het programma Pluripotent Stem cells for Inherited Diseases and Embryonic Research (PSIDER) is bedoeld voor biomedisch onderzoek met geïnduceerde pluripotente stamcellen (iPS). Binnen het programma zijn naast (bio-)medisch onderzoek ook maatschappelijk verantwoord innoveren vraagstukken (MVI) een sterk aandachtspunt.
Om verschillende wetenschappelijke disciplines elkaar te laten vinden, bieden we onder andere een besloten LinkedIn-groep aan voor kennismaking en discussie. Ook heeft een aantal wetenschappers een pitch ingediend. Bent u geïnteresseerd in samenwerking binnen één van de onderstaande onderzoeken of heeft u antwoord op de MVI vraagstukken? Laat dit dan weten via translational@zonmw.nl.
De pitches vindt u op deze pagina.
Inhoud
- Discordant Monozygotic Twinning in Beckwith-Wiedemann Syndrome
- Engineering improved patient-specific iPSC-derived models for neurodegenerative disease and the ethical implications thereof
- Dissecting molecular mechanisms underlying GNA01 and other epileptic disorders: preclinical models for identification and validation of therapeutic targets
- Pluripotente cel en genome editing expertise aangeboden
- Moleculaire mechanismes van zeldzame rode bloedcelziekten: van fundamentele kennis naar nieuwe behandelingen
- From stem cells to human blastoids
- Patient-centered development of models for inherited skin disorders
- Modeling thyroid hormone signaling disorders
Discordant Monozygotic Twinning in Beckwith-Wiedemann Syndrome
Samenvatting
Beckwith-Wiedemann Syndrome (BWS) is an overgrowth congenital disorder with an increased frequency of monozygotic (MZ) twinning, in which the MZ twins predominantly are discordant for BWS. The aetiology of this increased MZ twinning frequency remains unknown. Examining this unique phenomenon is expected to lead to a better understanding of the process of MZ twinning, epigenetic methylation disturbances, and human embryonic pluripotency. We hypothesize that by investigating the molecular and phenotypic differences of naïve and primed induced pluripotent stem cells (iPSCs) derived from skin fibroblasts of discordant BWS MZ twin pairs the pathogenesis of this process can be uncovered.
Projectleider
Marie van Dijk, PhD
Amsterdam UMC, locatie AMC, Laboratorium voor Voortplantingsbiologie
Projectleden tot nu toe
Saskia Maas, MD
Amsterdam UMC, locatie AMC, Klinische Genetica
Bruno Reversade, PhD
A*STAR Singapore, Institute of Medical Biology
Welke kennis (technologisch, MVI, medisch-biologisch) mist u nog in uw consortium?
MVI, eventueel technologisch
MVI vraagstukken die u verwacht in de loop van uw project:
Alle vraagstukken
Engineering improved patient-specific iPSC-derived models for neurodegenerative disease and the ethical implications thereof
Samenvatting
iPSC technology is well-suited for studying genetic (developmental) diseases, but modelling of adult-onset neurodegenerative diseases was less successful, likely due to the rejuvenation that occurs during iPSC reprogramming and the lack of age- or frailty-associated factors that trigger such diseases.
We will:
- develop iPSC models for (induced) frailty to study disease-related phenotypes with versatile, robust, quantitative monitoring platforms.
- employ robotics to culture and phenotype cohorts of iPSCs derived from MS, frontotemporal dementia and polyglutamine patients to unravel factors that result in loss of CNS resilience and drive pathology
- exploit these models to explain variability in etiology and design intervention strategies
- investigate the ethical implications of our findings for patients
Projectleider
Harm Kampinga
University Medical Center Groningen, University Groningen
Projectleden tot nu toe
Bart Eggen
University Medical Center Groningen, University Groningen
John van Swieten
Erasmus University, Rotterdam
Floris Foijer
University Medical Center Groningen, University Groningen
Peter Heutink
DZNE, Tuebingen, Germany
Welke kennis (technologisch, MVI, medisch-biologisch) mist u nog in uw consortium?
We are inviting a social scientist (MVI) to help us address the ethical considerations that follow from our findings and to implement our models and findings from our models in the social domain.
MVI-vraagstukken die u verwacht in de loop van uw project:
Our models could reveal the severity of a genetic predisposition (frailty factor(s)) and thus lead to better prognosis and prediction of the age of onset for the disease. There is a considerable variation in age at onset within families with hereditary FTD. As clincial trials will come up the near future, it will important to come to a better estimation of age of disease, as this will have an effect on the time to start such treatment. Do carriers of such predispositions want to be informed as it might burden them long before disease onset. Will patients or carriers use this information when deciding to have children. How important is the age of onset for a carrier/patient? For instance, are 50 predicted healthy years enough to have your children carry the same predisposition? If a preventive strategy would be found, when to start with treatment and how to balance risk and benefits.
Dissecting molecular mechanisms underlying GNA1 and other epileptic disorders: preclinical models for identification and validation of therapeutic targets
Samenvatting
Epilepsies are diseases of episodically dysfunctional neuronal circuit activity in the brain. Epilepsy is currently estimated to affect over 65 million individuals worldwide, constituting one of the most prevalent neurological diseases. While some types of epilepsies present with mild seizures occurring early on in neonates or infants, others present with severe epileptic encephalopathies (EE) with intellectual disability, and other multi-organ comorbidities. The GNAO1 gene encodes the alpha-subunit of the guanine nucleotide binding protein. Mutations in GNAO1 result in a rare childhood neurological disorder with a broad clinical spectrum. These mutations are always de novo. One of the phenotypes associated with GNAO1 mutations is early onset childhood epilepsy (Ohtahara syndrome). The pathophysiology is still largely unknown and a curative treatment does not exist. Since GNAO1 mutations are always de novo, prenatal diagnostics are mostly not an option. The lack of understanding of the molecular mechanisms underlying the disorder has hindered the development of targeted therapies for this and other epileptic disorders. Our consortium will characterize the molecular pathways involved in diseases with a broad range of epileptic phenotypess using 2D and 3D neuronal differentiation of patient-derived induced pluripotent stem cells (iPSC). A deep phenotyping clinical study will provide additional insights into the broad clinical manifestations of the studied diseases. Our ultimate goal is to identify druggable pathways to restore normal functioning of the neural system.
Projectleider
Prof. dr Frank Baas
LUMC, Dept of Clinical Genetics
Projectleden tot nu toe
Dr. Harald Mikkers
LUMC, Dept. Of Cell & Chemical Biology iPSC hotel
Prof. Dr. Ype Elgersma
Dept of Neuroscience Erasmus MC
Welke kennis (technologisch, MVI, medisch-biologisch) mist u nog in uw consortium?
This consortium has expertise in the study of epileptic disorders, iPSC generation and iPSC-based disease modeling, RNAseq and pathway analysis and clinical expertise. We also have good contacts with the Dutch epilepsy and national and international GNAO1 patient’s advocacy groups. Together we have the expertise to meet the goal of identifying new therapeutic opportunities for the studied diseases. Although the basic knowledge about epileptic disease will be generated in this project, there is need to integrate the consequences of this knowledge.
MVI vraagstukken die u verwacht in de loop van uw project:
Using the active participation of the stakeholders (patient advocacy group such as: Epilepsie Vereniging Nederland, Dutch GNAO1 foundation) the design process of the consortium will be adjusted. Stakeholder input is considered crucial MVI implementation. We will setup a consortium that will integrate researchers who are able to help with answering the questions of the stakeholders. For now the possible questions coming from the stakeholders pertain:
- To the quality of life/extension of life issues of potential new therapeutics
- Whether there is need to establish European reference centres for rare types of epileptic disease
- What are the legal ramifications of providing patient and family material for these type of studies that may result in new therapeutic options.
- How do we ensure that any new scientific insights and technological advancements will be of actual benefit of patients and how can we prevent that new IP is being buried by pharmaceutical companies due to changing company policies.
Pluripotente cel en genome editing expertise aangeboden
Samenvatting
Hohenstein heeft een achtergrond in embryonale nierontwikkeling, embryonale nier stamcellen en Wilms’ tumoren, en heeft als hoofd van de Transgenese Faciliteit Leiden unieke ervaring met het ontwerpen en ontwikkelen van mutante muismodellen en alle mogelijke varianten van CRISPR/Cas9 genome editing. Mulder is kindernefroloog gespecialiseerd in ontwikkelingsafwijkingen met brede ervaring in non-invasieve, patiënt-specifieke iPSC productie en nier organoids. Samen beslaat hun expertise het hele gebied van iPSCs, gene targeting en editing, organoids en indien noodzakelijk muis ES cellen en transgene modellen. Deze expertise wordt aangeboden voor nier, maar ook andere projecten.
Moleculaire mechanismes van zeldzame rode bloedcelziekten: van fundamentele kennis naar nieuwe behandelingen
Samenvatting
Rode bloedcellen verzorgen het zuurstoftransport in ons lichaam en zijn essentieel voor onze gezondheid. Er is een grote verscheidenheid aan zeldzame erfelijke ziektes die het normale functioneren van de rode bloedcellen belemmeren. De daarbij betrokken genen hebben diverse moleculaire functies zoals zuurstoftransport, heemsynthese, celstructuur, energievoorziening, eiwittranslatie en DNA reparatie. Het is vaak niet bekend waarom de ziekte-veroorzakende mutatie zo’n groot effect op de rode bloedcellen heeft. Met behulp van iPS cellen van patiënten gaan we onderzoeken waarom de vorming van rode bloedcellen niet goed verloopt, de effectiviteit van gencorrectie testen, en nieuwe toepassingen voor bloedtransfusie ontwikkelen.
Projectleider
Prof. dr.J.N.J. (Sjaak) Philipsen
Erasmus MC afdeling Celbiologie, Rotterdam
Projectleden tot nu toe
Prof. dr. G. (Gerald) de Haan
ERIBA / UMCG, Groningen
Dr. M.M. (Marieke) von Lindern, Dr. E. (Emile) van den Akker en Dr. E.M. (Eva-Maria) Merz
Sanquin Research afdelingen Hematopoëse en Donorstudies, Amsterdam
Dr. L.J. (Luis) Cruz Ricondo en Dr. C. (Christina) Eich
LUMC afdeling Radiologie, Leiden
Welke kennis (technologisch, MVI, medisch-biologisch) mist u nog in uw consortium?
- Technologisch: reactortechnologie voor opschalen celkweek. We denken aan een technische universiteit zoals TU Delft.
- MVI: patiëntenorganisaties, we denken aan OSCAR, Stichting Zeldzame Bloedziekten en Sikkelcelfonds.
- Medisch-biologisch: clinici ontbreken nog. We denken aan hematologen, transplantatieartsen en klinisch genetici verbonden aan UMC’s.
MVI vraagstukken die u verwacht in de loop van uw project:
De discussie rondom het gebruik van iPS cellen in onderzoek en de slag naar toepassingen in de kliniek.
Acceptatie van transfusieproducten die uit een bioreactor komen in plaats van donorbloed.
Een model voor een constructieve dialoog tussen de onderzoekers, clinici, bloeddonors en patiënten.
Acceptatie van genreparatie en innovatieve genexpressie technieken in het onderzoek en in klinische toepassingen, op het terrein van zeldzame rode bloedcelziektes in het bijzonder.
From stem cells to human blastoids
Samenvatting
In this proposal, we aim at building a human blastoid that recapitulates key molecular and functional aspects of the human blastocyst-stage embryo. Faithful induction of blastocysts lineages is key here for which we will develop microengineered tools. This includes high-throughput embryo culture and analysis platforms to identify and study new instructive molecular and biophysical cues and microfluidic chips to generate controlled gradients of soluble factors over 2D and 3D cell constructs. This unique combination will allow us to decouple lineages and study their induction, progression, plasticity and interaction in a modular fashion.
Projectleider
Prof. Clemens van Blitterswijk
MERLN Institute, Maastricht University
Projectleden tot nu toe
Dr. Stefan Giselbrecht
MERLN Institute, Maastricht University
Dr. Erik Vrij
MERLN Institute, Maastricht University
Prof. Guido de Wert
Metamedica, School for Public Health and Prim Care, Fac. Health, Medicine and Life Sciences, Maastricht University
Welke kennis (technologisch, MVI, medisch-biologisch) mist u nog in uw consortium?
- Expertise on human naive pluripotency.
- Expertise on genetic engineering / genome editing.
MVI vraagstukken die u verwacht in de loop van uw project:
Societal questions
- How can we form embryo models that represent the worldwide genetic diversity?
- How could the ‘Embryowet’ be interpreted / apply to stem cell-based embryo models? Would these models require a legal amendment?
Implementation
- How can embryo models be of value for the clinic? And what steps / milestones need to be taken for their acceptance as a practical model in the clinic?
Organisation
- How can we most effectively communicate with society on the scientific progress and implications of human embryo models?
Patient-centered development of models for inherited skin disorders
Samenvatting
Inherited skin disorders range from life-threatening blistering problems at birth to symptoms and comorbidities that need life-long management, e.g. infections, itch, sweat and temperature regulation. Understanding disease mechanisms using patient-derived models is the prerequisite to develop proper patient care and treatment in a general yet personalized manner. To address the challenges in this patient-centered project, our consortium integrates leading experts in genodermatology, patient-derived induced pluripotent stem cells, human skin organoids, in-depth molecular analyses and experts in ethical and social sciences. We aim at understanding the pathological mechanisms by developing proper tools for disease modelling and testing of therapeutic interventions.
Projectleider
Jo Huiqing Zhou
Radboud University, Molecular Developmental Biology
Projectleden tot nu toe
Ellen van den Bogaard
Radboudumc, Laboratory for Experimental Dermatology
Antoni Gostynski
Maastricht UMC, Dermatology
Marieke Bolling
UMC Gronginen, Dermatology
Christian Freund/Karine Raymond
LUMC, hiPSC Hotel
MVI partners:
Luca Consoli, Lotte Krabbenborg, Radboud University, Science in Society
Patient organizations
Welke kennis (technologisch, MVI, medisch-biologisch) mist u nog in uw consortium?
High throughput screening expertise and tools
MVI vraagstukken die u verwacht in de loop van uw project:
- From lab-world to life-world: investigate the various tensions between scientific and technological possibilities developed by scientists and biotech companies on the one hand and expectations and concerns of users (patients, clinicians and public in general) on the other hand through (social) media analysis, focus groups and individual interviews with patients, patient organizations and clinicians
- Empirical approach to ethical and societal issues pertaining hiPSC: Analyses have shown that different stakeholders have different perspectives, interests and needs regarding how to deal with ethical and societal issues. In the MVI part of this project, we will 1) inquire into the needs and concerns of each stakeholder group mentioned above with regard to the ethical and societal issues; 2) analyse the (dis)agreements between stakeholders with regard to how to address these issues, as an overview of the different perspectives is still lacking
- Informed consent: review of current procedures on the basis of both empirical research as recent insights on what counts as ‘good’ informed consent
- Future scenario’s: Design and organize multistakeholder-scenario workshops in which clinicians, patients/patient representatives, scientists, biotech companies and insurance companies will participate. The overall aim is to stimulate mutual learning with regard to envisioned promises and concerns related to hiPSC.
Modeling thyroid hormone signaling disorders
Samenvatting
Thyroid hormone is crucial for brain development as illustrated different neurodevelopmental disorders due to disrupted thyroid hormone signalling in the brain (e.g. defects in thyroid hormone transporters or receptors). The mechanisms of normal or abnormal thyroid hormone signalling in human brain development are poorly understood due to the lack of appropriate human models.
We plan to employ patient-derived iPSCs to understand cell-type specific dysregulation of thyroid hormone homeostasis underlying the neurological phenotypes of thyroid hormone signalling disorders. With varying phenotypes (development vs degeneration) in the different disorders and different neural cell types affected, we seek for a long-term fruitful synergist collaboration with other groups to advance understanding of brain function.
Projectleider
Naam: Edward Visser & Nilhan Gunhanlar
Instituut: Erasmus MC
Projectleden tot nu toe
Femke de Vrij & Steven Kushner
Erasmus MC
Welke kennis (technologisch, MVI, medisch-biologisch) mist u nog in uw consortium?
Our lab has a longstanding interest in thyroid hormone biology. We fulfil a worldwide expertise role in this field and we are in the advantageous position to have clinical data and iPSCs from all thyroid hormone signalling disorders.
The consortium being formed benefits from the participation of the Dept of Psychiatry (Erasmus MC), which has its focus on the genetics and biological mechanisms underlying neurodevelopmental and psychiatric disorders, through a combination of clinical, translational, and fundamental neuroscience approaches. The Kushner lab has a strong track-record in elucidating pathophysiological mechanisms underlying neuropsychiatric disorders. In particular, his lab has proven high-quality research in the application of human iPSCs to model rare neurodevelopmental disorders, with recent examples published.
However, the thyroid lab is relatively new to the field of iPSCs and we would like to engage with other groups who are specialized in neural cell lineages. We would like to invite groups who are experienced in astrocyte and/or neuronal cell studies.
In addition from bringing in specific expertise on the disorders, our background could be valuable to any group in the (neural) iPSC field. This is because differentiation protocols neural cells require the B27 supplement, which includes the active thyroid hormone T3; T3 action is a critical switch in proliferation vs differentiation. However, the optimal dosing of T3 on neural differentiation protocols has never been studied, likely as this has been regarding as ‘’just another growth factor’’ in the iPSC field. Given the cell-type and time-specific effects of thyroid hormone, it is plausible that different T3 concentrations are needed for further optimizing such protocols. Therefore, this project may shed light on understanding the contribution of T3 to the differentiation protocols and has the potential to revise various differentiation protocols.
It is our hope that our project will reveal unprecedented information of thyroid hormone in a human model reflecting brain development, but also will provide input for further optimization of any differentiation protocol.
MVI-vraagstukken die u verwacht in de loop van uw project:
We use patient-derived cells from various rare diseases as well as controls from unaffected family members. This poses different challenges with ethical and legal aspects.
With the increasing awareness of rare diseases as a whole, the impact of using cells from their beloved ones can be larger than anticipated (e.g. revealing the far reaching consequences on molecular level can have huge impact on families). Given the rarity of the disease, even anonymized data may result in identification of patients, which may have huge legal and ethical consequences (conflict of adhering to principle of law vs advancing knowledge on the disease with potential treatment possibilities).
The involvement of patients (or family members) in such discussions is not well developed. We look for a group (groups) who can provide input on the ethical, social and possibly legal implications using our scientific studies as a prototypic case.
ZonMw stimuleert gezondheidsonderzoek en zorginnovatie. ZonMw financiert gezondheidsonderzoek en stimuleert het gebruik van de ontwikkelde kennis - om daarmee de zorg en gezondheid te verbetereZonMw heeft als hoofdopdrachtgevers het ministerie van VWS en NWO.