Ongoing research

Our retinal projects are organised around five major themes:

Robust generation of 3D laminated retinae from human pluripotent stem cells

The generation of human retinal tissue from stem cells has been a pioneering breakthrough.

Pluripotent stem cell derived retina: immunocytochemistry analysis at day 35 of differentiation.
Click the image to enlarge.

X

The generation of human retinal tissue from stem cells under laboratory conditions has been a pioneering breakthrough which has transformed the field of ophthalmic research, yet this approach needs to be further developed so that human retinal tissue can be produced more efficiently and reproducibly from different patient's stem cells.

Our group has developed a unique method to convert both human embryonic stem cells and iPSCs, collectively termed human pluripotent stem cells, into fully laminated retinae containing many of the different retinal cell types. Using this tissue as a resource, our aims are to:

This is an exciting, high risk and high gain project that is projected to enhance the treatment of retinal degenerative disease. Moreover, the efficient generation of retinal "mini-organs" in a dish will allow us to create models of retinal disease that can be used for large scale drug testing and clinical cell-based transplantation trials, all of which have not been possible so far due to difficulties in accessing patient-specific retinal tissue.

This project is funded by the European Research Council and RP Fighting Blindness, UK and is being developed in close collaboration with Dr. Evelyne Sernagor and Dr. Geritt Hilgen at the Institute of Neuroscience and Prof. Susan Lindsay at the Institute of Genetic Medicine (Newcastle University).

Modelling of AMD, RP and m.3243A>G mitochondrial DNA mutation using a patient specific iPSC approach

Our approach to deriving patient specific induced pluripotent stem cells (iPSC).

Retinal Disease modelling with iPSC, Retinitis Pigmentosa (RP) and Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (m.3243A>G mitochondrial DNA mutation) using a patient specific induced pluripotent stem cell (iPSC) approach.

In the last three years we have derived iPSCs from AMD, RP and m.3243A>G mitochondrial DNA mutation patients and have generated patient-specific photoreceptors and retinal pigmented epithelial cells which we are using to understand the cause and progression of these diseases as well as developing targeted strategies for moving forward with therapeutic interventions.

These projects benefit from Fight for Sight UK, Macular Society UK, EbiSC, Bayer, AHSN, Novartis and Newcastle Health Charity funding and are underpinned by close collaborations with Dr. David Kavanagh (Newcastle University), Prof. Colin Johnson (University of Leeds), Dr Sushma Grellscheid (University of Durham), Dr. Viktor Korolchuk (Newcastle University) and Dr. Patrick Yu-Man (Newcastle University).

Improving photoreceptor delivery in vivo

Despite our increasing knowledge, there is a lack of information about the optimum method of cell delivery.

Despite our increasing knowledge of the type and developmental stage of cells that may be transplanted in order to treat retinal disease in animal models, there is a lack of information about the optimum method of cell delivery. Current techniques using fine bore cannulas can damage the cells during injection to the point where they lose function and/or viability.

Dead or dying cells have significant detrimental effects on the living cells around them. In addition, some cells are either retained within the cannula or lost by reflux following injection. This means that significantly fewer functional cells than the optimal prescribed dose are delivered subretinally. Furthermore, once the cells have been delivered they can often assume an uneven distribution with clumping and aggregation a common occurrence, rather than forming an evenly dispersed layer which would optimally be desired.

We are investigating the process of the delivery of cell suspensions into the subretinal space with the aim of overcoming these problems using a variety of different approaches. We are working with industry and major grant funding bodies which we will feed into our long term aim of developing our own cellular therapies to help restore vision to those who are blind as a result of outer retinal disease.

Clinical trials of cellular therapies

We are actively participating in current clinical trials of cellular therapies.

Our group is also actively participating in current clinical trials of cellular therapies and Mr Steel participated as a Phase 1 principal investigator in the ground breaking Ocata (now Astellas Institute of Regenerative Medicine) therapeutics trial of embryonic stem cell-derived RPE cell transplantation into the subretinal space in patients with Stargardt's macular dystrophy.

Mr. Steel is developing links with other companies involved with subretinal cellular therapies to bring these innovative new treatments to the clinic in the fastest possible time frame.

Understanding the development of the human eye

Expression of IMPG1 in developing human retina at six weeks post-conception.
Click the image to enlarge.

X

Vision loss can occur through the effect of faulty genes we inherit from our parents as well as the accumulation of damage and the effect of various diseases throughout our lives.

Our ability to prevent and treat vision loss is closely linked with our knowledge of "how eyes form" and when and what is likely to go wrong. Our eyes develop mostly before birth and the availability of tissue to study from this time period is very limited. Our group is in a unique position, having access to normal eyes through a tissue resource jointly established in our Institutes which collects samples from aborted embryos and fetuses with the mother's consent (www.hdbr.org/).

Our aim is to use these samples to understand how and when parts of our eyes form, how they function and interact together and the role of genes that cause loss of vision when faulty. This project benefits from close collaboration with Prof. Susan Lindsay's group at the Institute of Genetic Medicine in Newcastle, Human Developmental Biology Resource (HDBR) and funding provided by the European Research Council (ERC).

Institute of Genetic Medicine and Institute for Ageing

Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne, NE1 3 BZ. United Kingdom

Tel: +44 (0)191 241 8688
Email: majlinda.lako@ncl.ac.uk

 

Newcastle University