Our Research in a nutshell

Age-related Macular Degeneration (AMD)

Age-related macular degeneration (AMD) affects 4% of the population over 60. It is a severe eye disease that that results in blurred central vision or loss of central vision. For 90% of patients there is no cure. According to recent surveys, AMD patients experience loss of quality of life compared to Alzheimer’s Disease.

Early stages of AMD are characterized by non-degradable metabolic retinal waste, called drusen, that accumulates between specific layers in the retina and causes damage that progressively and irreversibly yields loss of essential retinal cells and layers.

There are 2 types of AMD: dry and wet. Most people with AMD have dry AMD (also called atrophic AMD). This is when the macula gets thinner with age. Wet AMD (also called advanced neovascular AMD), is a less common type of late AMD that usually causes faster vision loss. Any stage of dry AMD can turn into wet AMD — but wet AMD is always late stage. It happens when abnormal blood vessels grow in the back of the eye and damage the macula. There is no cure for dry AMD, while a delaying therapy for wet AMD exists.

In one research project, we aim to generate AMD-in-a-dish: a complete model of AMD In vitro, by means of a state-of-the-art 3D cellular bioprinter, in which we combine stem cell based multilayered retinal cell types including the vascular components with the toxic deposits that make up the drusen.  In 2022, we reached proof-of-concept for this new and human representative AMD model. This allows subsequently to assess the development of precisely directed therapy for AMD.

We also have a regenerative medicine project which is aimed at therapeutic transplantation of stem cell derived RPE to the subretinal space of in-house developed animal models for AMD.

The relevant analyses are based on relevant techniques readily available in our lab, such as transcriptomics, proteomics, metabolomics, and advanced microscopical techniques, and for the animal models non-invasive techniques SLO, OCT, ERG and visual behavioral tests.

 Gyrate Atrophy (GACR)

Gyrate Atrophy of the Choroid and Retina (GACR) is a rare genetic metabolic disease that is caused by a mutation in the gene encoding the protein OAT (ornithine aminotransferase). The resulting shortage in OAT leads to an excess in the amino acid ornithine, which in turn leads to progressive loss of vision. Very little is known about the underlying mechanisms and players in GACR, and the only available interventions are dietary based, which may be individually helping to slow down some aspects of the disease, but have not been proven robust.

In our research we have generated patient-derived stem cell lines as well as Crispr/Cas9 mutant ESC lines. The differentiation of the various stem cells into the retinal pigment epithelial (RPE) cell layer, and into 3D self-organizing retinal organoids, is expected to shed more light on the molecular and cellular events that underlie the progressive blindness caused by dysfunction or absence of OAT. Furthermore they will also aid in determine if and understanding why dietary interventions can slow-down the disease in some patients.

The detailed analyses at all omics levels, as well as more specific hypothesis-driven research questions, will not only boost the pathophysiological understanding of GACR, but also the development of future therapy design.

Clinical co-supervision: Prof dr. Clara van Karnebeek, Prof dr. Camiel Boon

This research project is embedded in the Emma Center for Personalized Medicine AUMC: Gyraat Atrofie – Stichting Steun Emma Kinderziekenhuis

https://gyrate.unitedformetabolicdiseases.nl/

Albinism

Albinism is a clinically and genetically heterogeneous disorder characterized by lack of melanin pigment. Albinism leads to life long vision impairment, as well as higher susceptibility of skin cancer. In the African population patients experience life-threating discrimination. Ocular albinism is characterized by foveal hypoplasia, resulting in blurred vision and aberrant crossing of the optic nerve fibers at the optic chiasm. this results in reduced binocular vision and strabismus. Based on the genes involved in albinism and their known functions in the eye or pigmentation in general, we have generated a new hypothesis for one single melanosomal pigmentation pathway in the eye encompassing all 22 disease disease genes. This pathway is most likely relevant for multiple retinal disease, where retinal pigmentation abnormalities occur.

Our research encompasses the detailed mechanistic issues of the disease in the relevant retinal cell layer (the retinal pigment epithelium; RPE) that we generate from a wide variety of patient-derived stem cells as well as Crispr/Cas9 generated mutants of various putative players in the pigmentation pathway. In addition, the nerve (mis)routing and a number of additional aspects that are consequential to the pigmentation pathway hypothesis, are studied with specific neuronal differentiations and 3D retinal organoids derived from the various genetic stem cells. These analyses are done with with all techniques available in our lab, encompassing various omics, advanced microscopy, and electrophysiology

Clinical co-supervision: Prof dr. Maria van Genderen (Bartimeus)

Glaucoma

Glaucoma is a heterogeneous and multifactorial group of eye diseases that result in insidious damage of the retina and optic nerve, leading to vision loss. It is the second cause of legal blindness world-wide. Several drugs exist to lower glaucoma-related IOP (intraocular pressure) and slow down the disease. However, usually irreversible retinal damage has already occurred before the disease is diagnosed. The pathophysiology is largely unknown.

In our research we aim to decipher the molecular genetic etiology with functional studies using patient derived stem cells and retinal organoids that represent the key cellular components and interactions.

In addition, we made Crispr/Cas9 mutated embryonic stem cells to further model the early molecular events leading to the disease. Those are used to grow the retinal ganglion cells and to generate an optic nerve model. Eventually the cellular glaucoma models will allow functional studies and are expected to result in the development of personalized medicine.

The analyses are based on the readily available omics in our lab as well as advanced microscopy techniques and in vitro electrophysiology.

This project is embedded in a long-term (inter-)national collaboration primarily funded by the EU programs EGRET (2015-2021), EGRET+ (2016-2020) and EGRET-AAA (2022-2026), the latter focusing on late stage glaucoma.

Co-supervision: Prof dr. Nomdo Jansonius, Prof dr. Frans W. Cornelissen, dr. Xavier Nicol (Sorbonne, Paris).

 Retinoschisis (XLRS)

X-linked juvenile retinoschisis (XLRS) is a degenerative retinopathy affecting boys and men. It is typically diagnosed in childhood, in some cases as early as three months of age. The phenotype varies from progressive vision loss throughout lifetime, to relatively stable reduced vision. The disease is caused by mutations in the gene RS1 encoding retinoschisin. This protein is important in the development and maintenance of the retina, and its loss of function leads to splitting of the retinal layers (schisis). The molecular and cellular mechanisms involved are still unknown and therapy is not available.

In our research we use patient-derived induced pluripotent stem cell lines as well as Crispr/Cas9 generated mutant embryonic stem cell lines in order to get a deeper understanding of the pathobiology. Retinal organoids made thereof present with schisis allowing the development of therapeutic approaches based on gene-editing, and/or AAV-based gene augmentation.

The analyses are based on relevant techniques readily available in our lab, such as transcriptomics, proteomics, metabolomics, and advanced microscopical techniques.

Co-supervision: Prof dr. Camiel Boon, clinical co-supervision: dr. M. van Schooneveld

Retinitis Pigmentosa (RP)

Retinitis pigmentosa (RP) is a progressive retinal genetic disease. Symptoms start in childhood, and comprise loss of night vision and peripheral vision, leading to tunnel vision and eventually blindness.  RP is untreatable, except for one subtype (“RPE65-RP”).

In our research, we develop experimental therapies for the LRAT subtype of RP (LRAT-RP).

To this end we examine “conventional” AAV-based gene therapy on LRAT-RP derived 3D retinal organoids, as well as gene therapy and stem cell-based cellular replacement therapy of part of the retina in an animal model of LRAT-RP.

The analyses of the animal model are based on non-invasive visual screening techniques, such as SLO-OCT, ERG, light-response behavior.