Professor Jane Sowden, Principal Investigator
Our aims are to define the genetic pathways that regulate eye development; to understand how these pathways are disrupted in childhood eye disease; and to apply knowledge of development, stem cell biology and genetics to devise strategies to repair and regenerate damaged tissue.
The eyes develop from the embryonic forebrain. By the sixth week of human development as the optic cups form, the neural retina begins to differentiate. We are interested in how morphogenesis, cell fate and differentiation are regulated and the related question of why these processes sometimes fail and cause developmental eye disease. Our research focuses on study of stem and progenitor cells that offer the potential for repair of retinal tissue. To investigate eye development in vitro we use human pluripotent stem cells to grow retinal organoids.
We conduct research in stem cell and developmental biology and genetics and cross-disciplinary studies bridging basic science and clinical research in ophthalmology. Our translational research aims to improve genetic diagnosis of childhood blindness and develop retinal cell replacement therapies to restore sight.
- Genetic basis of childhood eye conditions
In the UK, 1 in every 1,000 children is visually impaired or blind. More than a quarter of all cases are caused by congenital eye defects. For many, we do not know the genetic basis. Often a large number of genes are involved making diagnosis difficult. Many patients have developmental eye conditions as part of a syndrome. This highlights the importance of genetic testing which could help to predict symptoms that may appear as the syndrome progresses. Early genetic diagnosis can help with prevention and management of the condition.
We are working to discover the genetic basis of developmental eye conditions and improve genetic diagnosis. We use a range of experimental approaches (molecular biology, embryology, genetics and genomics) to explore the function and interactions of key genes (coding and non coding microRNAs) in vitro and in vivo.
To investigate the genetic basis of childhood blindness we developed a next generation sequencing multi-gene panel assay (the Oculome test). The test screens for mutations in more than 400 genes that are known to lead to eye diseases, including the conditions microphthalmia and coloboma, in which the embryonic eye fails to form completely, malformations of the anterior segment and glaucoma, and abnormal development and degeneration of photoreceptor cells. The oculome test improves the chance of providing a genetic diagnosis for childhood eye conditions. These tests were developed in collaboration with the North East Thames Regional Genetics Service Laboratory at Great Ormond Street Hospital (GOSH) and are offered nationally as part of the UK Genetic Testing Network diagnostic service.
We study the molecular and cellular processes essential for eye formation and apply transcriptomic and genomic analyses to identify regulatory genes. We are studying spatial patterning of gene expression and the process of optic fissure closure. We identified a novel homozygous mutation in a gene called SALL2, which causes ocular coloboma. This is the first report linking SALL2 mutation to coloboma.
Recruitment and collaborations
We invite children and families who have eye conditions with unknown causes to participate in our research. We collaborate with clinicians at GOSH and Moorfields Eye Hospital, and other national and international centres, UCL Genomics and GOSgene, and the Genomics England 100,000 Genomes Project. We link to patient advocacy groups such as MACS, (Microphthalmia, Anophthalmia and Coloboma Support), and the Aniridia Society.
- Retinal stem cell therapy
Inherited retinal degenerations affect 1 in 3000 of the population. At least ten percent of childhood blindness in the UK is due to retinal dystrophies that damage the photoreceptor cells. We aim to develop stem cell-based therapies to restore retinal function and improve sight.
We showed that transplanted photoreceptor precursors can improve visual function in mouse models of retinal disease. This work is a collaboration with Professor Robin Ali and Professor Rachael Pearson at the UCL Institute of Ophthalmology.
Our proof-of-concept experiments indicate that cell transplantation may be a feasible clinical treatment. We are pursuing development of photoreceptor transplantation therapy for the treatment of retinal disease.
Generation of stem-cell derived photoreceptors for transplantation
Stem cell cultures offer the potential to generate unlimited quantities of photoreceptors to replace those lost through disease. We aim to prepare human photoreceptor precursor cells suitable for transplantation and define the molecular cues that allow transplanted cells to effectively repair the retina.
We differentiate human pluripotent stem cells into optic vesicles in a process that replays aspects of embryonic eye development. These optic vesicles form laminated retinal structures including rod and cone photoreceptors.
By comparing cone photoreceptors generated from stem cells with cone cells in vivo we defined the gene expression signature of human developing cone photoreceptor cells.
We are developing cell selection methods to purify photoreceptors from the retinal organoids for transplantation.
We use gene editing to manipulate gene function and label specific cell types in order to elucidate gene function and evaluate methods for retinal cell production and purification.
Induced pluripotent stem cells (iPSC) are stem cells, which can be generated from adult tissue including blood and skin cells. They provide us with an opportunity to study retinal tissue derived from a patient’s own cells.
We culture retinal cells and tissue: from embryos; and human tissue, which we first turn into iPSC. We use retinal tissue to investigate: the molecular mechanisms which regulate the specification and proliferation of retinal progenitor cells; the generation of retinal neurons from these progenitor cells; and the cellular and molecular changes elicited by gene mutations.
We are using patient-derived IPSC to study disease mechanisms and to identify pathways that could be targeted in order to delay retinal disease progression. We are analysing IPSC-derived from individuals with Usher syndrome and foveal hypoplasia (aniridia).
- Lab Members
- Ashwak AlShehri
- Lisa Hentschel
- Dan Holder
- Rachel Wong
- Valda Pauzuolyte
- Funders, Collaborators and Partners