Regenerative Medicine

Joints and cartilage – Develop novel regenerative therapies for OA and cartilage repair

Ambassadors: Ingrid Meulenbelt (i.meulenbelt@lumc.nl, MOLEPI) and Yolande Ramos (y.f.m.ramos@lumc.nl, MOLEPI)  

Cartilage implants are being engineered with the right zonal structure for implantation into osteoarthritis-related defects by using scaffolds repopulated with hiPSC-derived cartilage organoids. Herein we apply established robust hiPSC derived differentiation protocols to cartilage and bone organoid and develop strategies to implement hiPSC derived chondroprogenitors as sustainable ‘off the shelf’ cell source. Moreover, to determine and understand key modifiable factors that direct and maintain hiPS-cell differentiation into stable chondrogenic lineages more fundamental research is performed (temporal multi-modal single cell sequencing of hiPSC chondrogenesis) to advance the use of hiPS-cells towards clinical applications in joint diseases. For preclinical testing a wide variety of human biomimetic joint tissue models are developed. The range of complexity (osteochondral compartment on chip) and throughput (3D in vitro organoids in 96 well plates) of the models allows a flexible and efficient preclinical testing. If pre-clinical phases are successful, these will be further developed based on LUMC’s GMP-compliant hiPSC lines for clinical implementation. On the other hand regenerative medicine research in the RegMedTO theme is translating hiPSC derived MSCs (hiMSCs) as new opportunities for functional recovery of joint tissues. 

Pancreas – generating stem cell islets for treatment of type 1 diabetes

Ambassadors: Eelco de Koning (e.j.p.de_koning@lumc.nl, INT) and Françoise Carlotti (f.carlotti@lumc.nl, INT) 

The standard treatment for type 1 diabetes is self-administration of insulin via injections or pumps. For a small group of patients with very complicated type 1 diabetes, donor pancreas or donor islet transplantation can be performed. The LUMC is the only center in the Netherlands with a donor islet transplantation program which we started in 2007 (allogeneic islet transplantation). We also isolate and transplant islets from patients’ own pancreas if the pancreas needs removal because of a non-malignant condition (autologous islet transplantation). Understanding pancreatic islet biology and how to (re)generate and transplant islets are the main focus of our research program. Clinical research is focused on improving current human islet isolation and transplantation. In addition, we aim to protect and assess islet function in transplant patients and patients with damaged islet cells such as in type 1 diabetes.  Translational research focuses on human islet cell identity, islet survival and function. We develop strategies to generate new insulin-producing cells from adult progenitor cells or hPSCs. We have successfully established hPSC differentiation protocols that allow us to generate stem cell islets in a research setting. We aim to translate these research protocols to clinical compliance as a first step, so that stem cell-derived islet replacement eventually becomes clinically applicable routinely for all patients with type 1 diabetes. 

Kidney – Generating kidney tissue from stem cells for transplantation

Ambassadors: Siebe Spijker (h.s.spijker@lumc.nl, INT) and Cathelijne van den Berg (c.w.van_den_berg@lumc.nl, INT) 

At present, the only cure for end-stage kidney failure is a kidney transplant but only relatively few patients can be treated because of the shortage of donor organs. There are currently more than 600 patients on the waiting list in the Netherlands. Generating kidney tissue from stem cells or stimulating the intrinsic regenerative capacity of resident kidney stem cells, may contribute to Regenerative Medicine solutions for these kidney diseases in the future. This is being investigated by RegMedTO researchers. In addition, research is underway to analyze the kinetics of metabolism at the single-cell level in donor tissue to increase knowledge on donor organ health and resilience during the transplant and beyond, from the organ donation phase through its machine perfusion to its functionality in vivo.  Similar techniques will be implemented to monitor hPSC-derived kidney organoid functionality as this evolves and will be transferred to other organs that fall under LUMC’s organ transplant program. Finally, cell therapy is being investigated to reduce the burden of immune-suppressive drugs, by treatment with hPSC-derived mesenchymal stromal cells after kidney transplantation.

Lung – REpairing lung damage via reCOVery of stromal heAlth to restore respIRatory function

Ambassador: Anne van der Does (a.van_der_does@lumc.nl, LONG) 

RecovAir aims to improve the lifespan and quality of life of patients suffering from the progressive lung disease COPD (chronic obstructive pulmonary disease) by delivering technology-inspired disease-modifying treatment to achieve lung tissue repair and restore lung function. Specifically, we are establishing next-generation, controlled-release endobronchial delivery of micrometre-thin hydrogels to encapsulate stem cells, their exosomes and/or regenerative compounds in nanoparticles to transfer stromal regenerative potential to the damaged lung. RegMedTO theme researchers contribute to this aim with development of advanced organ-on-chip models to test these newly developed strategies.

Blood/Immune system – Hematopoietic stem cell transplantation

Ambassadors: Marieke Griffioen (m.griffioen@lumc.nl, HEM) and Jennifer Tjon (j.m.l.tjon@lumc.nl, HEM)

Patients with blood cancer or genetic defects in blood or immune cells can be treated by “hematopoietic stem cell” transplantation. In allogeneic hematopoietic stem cell transplantation, the diseased bone marrow of the patient is replaced by healthy stem cells from a donor. However, allogeneic hematopoietic stem cell transplantation is associated with the risk of “graft-versus-host disease”, a complication that is often fatal in which immune cells from the donor attack the host’s tissues. Regenerative medicine may provide several new options for treating blood disorders through manipulation of the patient’s own bone marrow stem cells, manipulation of donor-derived immune cells, and in the future through the use of universal donor hiPSC.  We are currently using basic science approaches to investigate these options. 

Reproductive organs – Maturing oocytes outside the body

Ambassador: Susana Chuva de Sousa Lopes (s.m.chuva_de_sousa_lopes@lumc.nl, ANA)  

Damage to the ovaries, for example,  following cancer treatment, invariably leads to loss of fertility as the immature eggs are damaged. For women with damaged ovaries, the normal production and release of egg cells cannot take place. RegMedTO researchers are investigating how, in the future, it may become possible to make an artificial ovary through regenerative medicine and mature human oocytes (for example collected from patients prior to oncology treatment) outside the body. 

Brain/Kidney – Evaluation of cell therapies using super-resolution ultrasound imaging

Ambassador: Franck Lebrin (f.lebrin@lumc.nl, NIER)

Cell and organoid therapies are advancing toward clinical use, yet few obtain market approval due to a lack of technologies for functional evaluation. One major challenge in medical imaging is the difficulty in obtaining non-invasive functional information deep in living organs across different size scales. Current modalities are limited to millimeter-scale resolution. We are currently investigating options to introduce non-invasive super-resolution ultrasound imaging modalities to monitor organ health and cell therapies. This involves the development of non-invasive functional ultrasound localization microscopy capable of detecting and characterizing the vasculature with high temporal (2 s) and spatial (6.5 µm) resolution, the microvasculature serving as a mirror of organ health status. We also introduce genetically encodable air-filled protein nanostructures expressed in hiPSC-derived cells to track them from the point of administration up to several months post-transplantation using ultrasound. Additionally, we develop innovative therapeutic agents enhancing vascular integrity to support engineered tissue homeostasis.

Pancreas – Ethical aspects of stem cell islet transplantation

Ambassadors: Lieke van Kempen (l.van_kempen@lumc.nl, E&R) and Nienke de Graeff (n.de_graeff@lumc.nl, E&R)

Recent advancements in stem cell-based medicine, supported by a growing body of pre-clinical evidence, suggest that transplantation of stem cell-derived pancreatic islets (stem cell islets) can provide a potential cure for type 1 diabetes. However, in order to develop a new therapy aimed at improving the quality of life of patients it is important to address the ethical challenges that come with the development of this new therapy, such as which individuals should be included in a first-in-human trial. In this project, we study the ethics of stem cell islet transplantation for diabetes type 1 using a combination of literature review, qualitative research with patients and other stakeholders, and normative analysis. Eventually, the project aims to stipulate recommendations for the responsible development of stem cell islets for type 1 diabetes.

Other – Immune evasive hiPSC lines

Ambassadors: Ton Rabelink (a.j.rabelink@lumc.nl, INT) and Arnaud Zaldumbide (a.zaldumbide@lumc.nl, CCB)

To counteract the immune rejection of hiPSC-derived products, a strategy is currently being designed for producing an immune evasive hiPSC line. Regenerative Medicine products derived from this line are expected to be universally applicable to all patients needing transplantation, providing the opportunity to deliver cost-effective, off-the-shelf products. 

Blood/Immune system – SCID

Ambassador: Frank Staal (f.j.t.staal@lumc.nl, IMMU)  

Understanding adult (bone marrow) stem cell biology and T cell development is the basis for developing new therapies for treating hematological and immune system disorders. Advanced molecular and cellular (20+ color spectral flow cytometry) techniques and genetic mouse models can be used for this research, as well as human cells from patients and healthy individuals.    

Regenerative medicine endeavors to transition from basic to translational and clinical research, specifically in preparing for clinical trials. A clinical trial for RAG1/SCID, where a mutation in the patient’s bone marrow is repaired in the laboratory and retransplanted into the patient, is currently underway. First patients have been treated with success.  

Blood/Immune system - Receptor gene-engineered T-cells

Ambassadors: Mirjam Heemskerk (m.h.m.heemskerk@lumc.nl, HEM), Marieke Griffioen (m.griffioen@lumc.nl, HEM) and Rosa de Groot (r.de_groot1@lumc.nl, HEM)

Receptor gene-engineered T cells are used to treat patients with leukemia, lymphoma, multiple myeloma, or other types of hematological malignancies. T cells are engineered with natural T-cell receptors (TCRs), artificial chimeric antigen receptor (CARs) or other type of receptors targeting lineage antigens, tumor associated antigens or neoantigens.     In addition, a company sponsored TCR T study for acute myeloid leukemia started June 2024, and an investigator initiated study with TCR T cells for multiple myeloma will start Q1 2025. 

Blood/Immune system - Stakeholder perspectives on considering stem cell therapy for patients with an inborn error of immunity

Ambassadors: Hilda Mekelenkamp (h.mekelenkamp@lumc.nl, WAKZ) and Nienke de Graeff (n.de_graeff@lumc.nl, E&R)  

Stem cell-mediated gene therapy and hematopoietic stem cell transplantation may provide curative therapies for patients with inborn errors of immunity, but using novel technologies such as stem cell-mediated gene therapy for new entities in minors also raises ethical questions and challenges. To identify and reflect on these ethical questions and challenges, insight into the perspectives of stakeholders on considering stem cell therapy, including hematopoietic stem cell transplantation and stem cell-mediated gene therapy, for patients with an inborn error of immunity is needed. These insights may inform the selection, decision-making, and consent process for clinical trials and in clinical use. This qualitative research project investigates the perspectives of patients with an inborn error of immunity, caregivers, referring and referred to healthcare professionals, researchers, ethicists, health economists, and policymakers through individual and group interviews.  

Eye – Inherited Retinal Disease (IRD)

Ambassador: Jan Wijnholds (j.wijnholds@lumc.nl, OOG)  

With the first approved gene therapy for inherited retinal disease, there are realistic prospects for new therapies for rod-cone dystrophies, rod dysfunction syndromes, cone and cone-rod dystrophies, cone dysfunction syndromes, macular dystrophies (MD), chorioretinal dystrophies, Leber congenital amaurosis (LCA), and Leber hereditary optic neuropathy (LHON). Adeno-associated viral (AAV) vector gene augmentation and gene editing techniques can be tested in genetic mouse models, human patient retinal organoids, and human donor retinal explants.    

These studies aim to go from fundamental to pharmaceutical and clinical phases, especially in preparing for clinical trials. Gene therapy studies for CRB1 (retinitis pigmentosa or RP, LCA), ABCA4 (Stargardt disease), RPGR (X-linked RP), USH2A (Usher syndrome) and ND4 (LHON) are initiated and for CRB1 are ready for pharmaceutical production and clinical safety testing.

Heart – Optogenetics

Ambassadors: Daniel Pijnappels (d.a.pijnappels@lumc.nl, HARTZ) and Twan de Vries  (a.a.f.de_vries@lumc.nl, HARTZ) 

The use of light-gated proteins (optogenetics) creates unmatched opportunities in gaining full control of a specific biological function, such as the electrical activity of cells. Optogenetic modulation of cardiac electricity is used to better understand and treat heart disorders by allowing researchers to precisely determine how much electrical current is produced by the heart at which location and for which duration. These unique features are exploited for mechanistic studies and to terminate ongoing arrhythmias. Although in the early phase of exploration, optogenetic interventions may also provide the basis for the development of shock-free ambulatory treatment options for cardiac arrhythmias. Although currently lacking, these options are attractive since they can circumvent the trauma for patients of giving high voltage shocks currently required for acute termination of heart rhythm disorders. Moreover, this would make patients no longer hospital-bound for treatment, thereby increasing their quality of life while reducing arrhythmia-related health care costs. This project closely collaborates with the Cardiovascular innovation theme.

Heart – Cardiomyocyte proliferation

Ambassador: Christine Mummery (c.l.mummery@lumc.nl, ANA) 

Cell transplantation is one way of replacing cells lost in organs like the heart following injury. An alternative is to induce endogenous cell cycle re-entry in postmitotic cells. In an ambitious program with internationally renowned cardiologists, we are revisiting this question for cardiomyocytes using mRNA approaches that are combined with specific miRNAs that ensure cardiomyocyte specificity. Clinical translation of mRNAs is regarded as safe following extensive use in Covid-19 vaccines, and short mRNA lifetime in cells should ensure just 2-3 divisions, envisioned as sufficient to increase cardiomyocyte numbers to a functional threshold. 

Skeletal Muscle – Muscular Dystrophies

Ambassador: Niels Geijsen (n.geijsen@lumc.nl, ANA)  

Muscle dystrophies are a collection of, sometimes fatal, genetic muscle disorders that severely impact the quality of life of patients. These include for instance Duchenne Muscular Dystrophy (DMD). Within the RegMedTO Theme for Innovation, new gene editing technologies are developed that bring the hope of restoring the quality of life by addressing function or regulation of the defective gene and preventing further muscle degeneration.  

Skeletal Muscle – Ethical aspects of gene therapies targeting DMD

Ambassadors: Isabelle Pirson (i.s.pirson@lumc.nl, E&R) and Nienke de Graeff (n.de_graeff@lumc.nl, E&R)

A non-viral, local CRISPR-cas9-based gene editing therapy is in development for intramuscular dosing in DMD. The development brings hope of a new treatment option for a subset of patients depending on the underlying mutation, but also comes with ethical and societal challenges such as when to commence first-in-human testing and how to ensure equitable access. Amongst others, this research project consists of a qualitative interview study investigating the perspectives of stakeholders such as patients, parents and caregivers, researchers and physicians. Overall, this research project aims to identify and understand these ethical and societal issues and provide recommendations to facilitate the responsible development of this gene editing therapy.  

Other –  Non-viral delivery systems

Ambassador: Niels Geijsen (n.geijsen@lumc.nl, ANA)  

For some tissues and gene therapy applications, viral delivery systems are not available, and they can be technically challenging or very costly. Alternative delivery systems to develop safe and sustainable gene therapies are under development.  

Other – Genome Editing

Ambassador: Manuel Gonçalves (m.f.v.goncalves@lumc.nl, CCB) 

Genome editing based on programmable DNA-targeting enzymes permits deleting, adding or “rewriting” the genetic instructions in living cells in a targeted fashion. As corollary, these technologies are having a significant impact on biological research and gene therapies. Indeed, rapid progress in the genome editing field is contributing to solving complex scientific questions and developing advanced gene and cell therapies for tackling genetic disorders with unmet medical needs and high societal burdens. Yet, critical improvements at the levels of gene-editing tool delivery and precision are in demand. Our research focuses on these two critical aspects by investigating; (i) viral vectors as delivery agents of gene-editing tools; and (ii) seamless gene-editing strategies which, in contrast to conventional approaches, do not generate mutagenic chromosomal breaks. The resulting findings and toolboxes are starting to be directed toward the modeling and correction of genetic disorders. These interconnected research lines seek to contribute to the treatment of monogenetic disorders of the striated musculature and hematopoietic system. 

Other – Viral Vectors

Ambassadors:  Rob Hoeben (r.c.hoeben@lumc.nl, CCB) 

Viruses are experts at taking over host cells, a process essential for viral progeny production. Following infection, major factors that determine the success of a virus in this process are its ability to exploit normal cellular processes and adapt to the host’s anti-viral measures. While the antiviral response is essential to protect us from potentially deleterious effects of viruses, the immune system can also thwart efficient gene transfer in vivo. Adenoviruses have been exploited as efficient means for in vivo gene transfer, but most humans have neutralizing immunity that rapidly inactivates adenoviruses. As a remedy, a large collection of new and unique adenoviruses (>40) was isolated from chimpanzee, bonobo, orangutan, and gorilla. To some of the isolates, no neutralizing activity was detected in human immunoglobulin pools. One of these was molecularly cloned and a tumor-cell selective derivative of this virus was generated (‘Goravir’) for use as oncolytic agent in humans. LUMC is now gearing up for outsourcing GMP production of Goravir, with brain cancer and pancreatic cancer as launching indications. This research is performed in close collaboration with researchers of the cancer theme. These new viruses may also be exploited as gene transfer vehicles for delivery of therapeutic genes of gene editing tools. 

Other – STRAIGHT-IN gene delivery platform

Ambassador: Richard Davis (r.p.davis@lumc.nl, ANA)  

Targeting genes into mammalian cells, such as pluripotent stem cells, can be a slow and challenging process, especially with larger constructs. Our new tool, STRAIGHT-IN, effectively addresses these challenges, enabling efficient integration of very large DNA cargoes (over 50 kilobases) into cells. This platform not only facilitates the targeting of large DNA fragments but also supports the simultaneous creation of multiple genetically modified cell lines. Its applications range from rapidly screening various gene therapy or synthetic biology vectors to developing extensive collections of human pluripotent stem cell lines containing different disease-linked genetic mutations. Such lines are valuable for disease modelling and advancing drug discovery efforts.