HUMAN GMP-COMPLIANT hiPSC line

hiPSC regenerative medicine products will be based on a clinical-grade hiPSC line, which is currently being produced as part of a collaboration between the iPSC-Hotel, the LUMC Center for Cell and Gene Therapy, and the Department of Nephrology. The line is expected to be available for producing clinical hiPSC-products in 2022.

Immune Evasion

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.

Kidney

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 an area being investigated by CTO 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 also be implemented to monitor hPSC-derived kidney organoid functionality as this evolves in the present research and will be transferred to other organs that fall under LUMC’s organ transplant program.

Pancreas

Daily insulin injection is currently the most widely used treatment for type 1 diabetes, although, for the most serious and unstable forms of the disease, a transplant of the entire pancreas or isolated islets of Langerhans is performed at LUMC. The islets of Langerhans are the main focus of both clinical and basic research projects. Basic research focuses on human islet cell identity, islet survival and function, and strategies to generate new insulin-producing cells from adult progenitor cells or hPSC. Clinical research is focused on improving current human islet isolation and beta-cell replacement therapy and assessing islet function and damage in patients with severe beta-cell failure (in particular type 1 diabetes).

Eye

There are presently few cures for hereditary or age-related forms of blindness. Damage to the cornea and retina can be caused by several diseases, and for some conditions, the incidence increases with age. Regenerative medicine can now offer new opportunities on which to base treatments or cures for selected causes of blindness. The CTO theme is investigating this as part of a national initiative (notably with the AMC and Radboud Hospital) to combat degenerative forms of eye disease.

Lung

There are presently few cures for hereditary or age-related forms of blindness. Damage to the cornea and retina can be caused by several diseases, and for some conditions, the incidence increases with age. Regenerative medicine can now offer new opportunities on which to base treatments or cures for selected causes of blindness. The CTO theme is investigating this as part of a national initiative (notably with the AMC and Radboud Hospital) to combat degenerative forms of eye disease.

Cartilage tissue engineering

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. If pre-clinical phases are successful, these will be further developed based on LUMC’s GMP-compliant hiPSC lines for clinical implementation.

Brain, nerves, muscle

Conditions affecting the brain, spinal cord, nerves, and muscles can affect people of all ages. Although the symptoms can be alleviated in some cases, there are few cures. In Regenerative Medicine, CTO researchers study the causes of these conditions, investigate possible treatments (cell-, drug- or gene therapy), and are working towards cures for a small number of specific diseases, often of genetic origin.

Heart, Cardiovascular, Pericytes

Treatment of heart disease currently involves advice on lifestyle changes such as weight loss or greater activity, medication, or surgery. Since Regenerative Medicine could offer opportunities to develop new treatments for various forms of heart disease, CTO researchers are using multiple human and mouse model systems to investigate several areas in which LUMC has historically carried out high-profile research. Some of the areas being investigated are promoting the division of resident cardiomyocytes in the heart, investigating how the lymph vasculature of the heart contributes to and may be a therapeutic target for, heart failure, and how vessel stabilization may benefit a multiplicity of (genetic) vascular diseases. This research has strong links and overlaps with the Cardiovascular theme.

Skin, Vascular system

Burn wounds, cancer, and vascular disease can all cause damage to our skin and vascular system. Regenerative medicine research can provide new opportunities for the treatment of these diseases. At LUMC, (adult and induced pluripotent-) stem cells from patients are being used to create somatic and genetic disease models amenable to screening for new or repurposed drug therapies. Diseases include several associated with blistering of the skin or poor drainage/oedema caused by dysfunctional skin lymphatics.

Ovary

Damage to the ovaries following cancer treatment, for example, 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. CTO Theme 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.

Liver and Intestine

Treatment of liver and bowel disease forms part of the clinical field of Gastroenterology and Hepatology. For the many diseases in these organs, current treatment usually involves advice on lifestyle changes such as diet and alcohol restrictions, medication, or surgery. Regenerative medicine research being carried out by CTO researchers could offer alternatives to treat digestive tract diseases, particularly conditions where inflammation is the underlying cause of disease. Specifically, the use of allogeneic hepatocytes is being explored as a novel approach to treating acute (or chronic) liver failure. Historically, research aimed at and including the clinical application of bone-marrow-derived mesenchymal stromal cells (MSCs) has been explored for the treatment of (refractory) inflammatory bowel diseases and complications, like perianal fistulas, with some success.

Blood

Patients with blood cancer or genetic defects in blood or immune cells can be treated with  “hematopoietic stem cell” transplantation. In this operation, the diseased bone marrow of the patient is replaced by healthy stem cells from a donor. However, 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, most notably through genetic modification of the patient’s own bone marrow stem cells, as described earlier, but also in the future through the use of universal donor hiPSC.

Inner ear

Artificial hearing aids in the form of an implanted device are presently the only treatment for many deaf patients. Regenerative medicine research performed by CTO researchers may provide ways in which damaged cells in the ear (such as the hair cells) can be replaced. One source of these cells is hiPSC and ongoing research is working towards this as a source of replacement hair cells. As we work towards a better understanding of the underlying causes of hearing loss and vestibular disorders, we may find new cures for certain forms of deafness and balance problems in the future.

Skeleton

Bones and joints are permanently damaged in diseases such as osteoarthritis, rheumatoid arthritis, bone tumors, and osteogenesis imperfecta. Current treatments mainly treat pain and other symptoms with limited success. Regenerative medicine research in the CTO theme is investigating new opportunities for research leading to functional recovery, including cell replacement and the inhibition of inflammation based on human model systems.

SCID

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 mouse genetic 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.

Optogenetics

The use of light-gated proteins (optogenetics) creates unique 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 the heart itself to generate electrical current for mechanistic studies and to terminate ongoing arrhythmias. Although in the early phase of exploration, optogenetic interventions may 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. This is also in close collaboration with the Cardiovascular theme.

Muscular dystrophy

Muscle dystrophies are a collection of, sometimes fatal, genetic muscle disorders that severely impact the quality of life of patients. New gene editing technologies bring the hope of restoring the function or regulation of the defective gene and preventing muscle degeneration.

Viral vectors

Viruses are experts at taking over host cells, a process essential for the production of viral progeny. 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. Regenerative medicine approaches are being developed that aim to use viral vectors to deliver gene therapy to, for instance, the retina, heart, muscle, and kidney. Among the most recent goals was that of delivering the gene therapy through vectors to which there is no pre-existing immunity in the human body.

Non-viral delivery systems

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.