Tissue engineering and regenerative medicine awards

Awarded to Stavros Loukogeorgakis for £74,973 as part of the new projects call 2023.

With this project we aim to develop a model of congenital diaphragmatic hernia (CDH), to provide a new tool to test treatments and research therapies for this complex condition.

CDH is a rare, life-threatening disease which affects 1/3,500 new-borns. CDH babies have a hole in the diaphragm muscle, causing the intestines and liver to move into the chest. This puts pressure on the lungs and stops them from developing. CDH has no effective treatment to date, and 30-50% of CDH babies do not survive.

If lung development can be improved, this can improve survival. Recently, our collaborators developed a new surgical treatment for CDH called FETO. FETO revolutionised the treatment of CDH, but predicted survival is still only 70%. Researchers are now looking for new drugs that can be used in combination, to improve the effects of FETO.

As of today, CDH research uses only animal models. However, none of these models fully reproduce CDH babies’ symptoms.

Recently, we studied in detail, the cells present in the amniotic fluid, the liquid present in the womb and surrounding the baby during pregnancy. In this fluid, we found stem cells from different organs, including the lung.

Starting from these cells we developed 3D cell spheres called organoids, which can be used to model the developing lungs.

In this new project, we want to generate organoids resembling the CDH lungs, and use these to predict patient outcomes and test novel treatments. In addition to predicting patient outcomes, our model would also help to define which drugs would work best for each single patient.

Our initial data on the project shows that we can create the lung organoids from CDH patients’ fluid, and that these show important differences to those from healthy babies, supporting their potential use as model of the disease.

Awarded to Jennie Chandler for £20,000 as part of the new projects call 2023.

ARC syndrome, or Arthrogryposis-renal dysfunction-cholestasis syndrome in full, is a rare childhood kidney disorder, caused by an error in the genetic code of a single gene. It causes kidney, joint and liver dysfunction, which together result in early fatality.

Currently, very little is known about how the kidney is damaged in ARC syndrome. What we do know is that important molecules, such as proteins and glucose, which the kidney usually reabsorbs back into the blood, are lost into the urine. Improving our understanding of why kidney reabsorption goes wrong is vital for discovering new treatments that can prevent this disruption and treat ARC syndrome, as well as many other kidney tubular disorders.

Commonly, mice are used to model human diseases. However, in ARC syndrome they do not offer a representative model of the kidney. Thus, this project aims to develop a representative human model of the kidney to study kidney tubular dysfunction in ARC syndrome. To do this, we will create a three-dimensional (3D) model to mimic the natural environment of the human kidney tubules where reabsorption occurs, which are called the proximal tubules. Then, we will genetically mimic ARC syndrome in the cells within the 3D proximal tubule and investigate the effects on tubular reabsorption.

The outcomes of this research will be the first to address the mechanisms underlying kidney dysfunction in ARC syndrome, whilst developing a human system that can be used to model other kidney tubular disorders and test potential therapeutics in the future.

Awarded to Michael Quail for £21,077 as part of the new projects call 2023.

Aortic coarctation is a localised severe narrowing of the main blood vessel to the body. This narrowing is life-threatening because it prevents normal blood flow to the body soon after birth. Affected babies require urgent surgery to relieve the narrowing and allow survival.

Surgical repair of aortic coarctation is usually very successful. However, in later life, patients typically develop high blood pressure, and this is associated with an increased risk of stroke and heart disease. Unfortunately, the reason for the development of high blood pressure is not well understood.

One possibility is that the nerves which control blood pressure in the aorta are damaged during coarctation repair. This is because the main aortic pressure sensors are in the same area as the coarctation narrowing, and they may be injured or inadvertently excised during surgical repair.

We would like to develop a new surgical technique to preserve these blood pressure sensors, by mapping their location at the time surgery, and using this knowledge determine if an adjustment of the surgical technique can be made to facilitate their preservation.

Project: Building mini organs for disease modelling.

Awarded to Lucy Holland for £96,699.

Also part of the Career Development Academy.

Project: Developing an implantable hepatic patch to treat a range of inborn liver diseases.

Awarded to Hassan Rashidi for £128,242.

Also part of the Career Development Academy.

The liver is essential to life as it produces proteins that are involved in key metabolic pathways and removes harmful toxins from the blood. Babies born with deficiencies in key metabolic pathways may die unless they receive an organ transplant. However, liver transplantation is far from an ideal therapy due to the shortage of donor organs, the high risk of the surgery especially in babies/children (mortality about 5%), the life-long problem of rejection, need for immunosuppression and the high risk of developing cancer and/or kidney failure.

Cell therapy is an attractive alternative to whole organ transplant as it avoids the need for an organ donor, major life-threatening surgery and the morbidity of post-surgery complications. However, cell therapies have yet to impact on clinical care due to the difficulty in producing, delivering, and maintaining sufficient numbers of cells to reverse the metabolic liver disease.

Human pluripotent stem cells (hPSCs) are cells with an unlimited ability for self-renewal, which can develop into functional liver cells, known as hepatocytes. I developed a novel approach to generate functional liver cells from hPSCs under the stringent conditions required for human cell therapies and these remained functional when transplanted into a mouse model of inborn liver failure.

I also developed two novel approaches to:

1- Encapsulate cells in a layer of gel making them suitable for transplantation to anybody without risk of rejection by the immune system.

2- Fabricate a polymeric patch to retain cells at the site of implantation for ease of removal/replacement if required.

The Hepatic Patch was implanted successfully in a model of inborn liver disease and achieved normal physiological level of a toxic metabolite within a month. In this project, I will move this technology forwards towards implementation, for the benefit of children with inborn liver disease.

Project: Investigating spatial and temporal tumour heterogeneity in neuroblastoma to improve surgical clearance and develop novel techniques for loco-regional control.

Awarded to Jonathon Neville.

Also part of the Career Development Academy.

Neuroblastoma is a paediatric cancer arising from neural tissue during embryonic development. It has varied clinical outcomes, from spontaneous remission to aggressive disease. Neuroblastoma causes 15% of all childhood cancer deaths and five-year survival rates for high-risk disease is 40 – 50%. Certain genetic mutations, changes in gene expression and altered interactions with the immune system are associate with poor outcomes in neuroblastoma. However, these changes vary significantly across a single tumour and this tumour heterogeneity changes over time.

Surgery is an important part of neuroblastoma treatment, but it can be difficult. The tumour often adheres to important structures, and it can be hard to differentiate tumour from healthy tissue. Fluorescence-guided surgery (FGS) uses probes that label tumour tissue to illuminate neuroblastoma intra-operatively. This makes it easier for surgeons to identify tumour tissue, enables complete resection and reduces complications. Some FGS probes under development for neuroblastoma have shown promise in pre-clinical studies, however the utility of these probes is limited by tumour heterogeneity and the effects of treatments prior to surgery (chemotherapy and immunotherapy).

There is little evidence investigating and linking the genetic, gene expression and immune system profiles in neuroblastoma over time. In this study, we will perform imaging-guided, multiple-site biopsies from diagnostic and post-treatment tumours. These samples will undergo genetic, gene expression, and immune system analysis. We will integrate these results to identify characteristics associated with poor outcomes. Tumour tissues will be analysed to identify new targets for FGS probes. By comprehensively mapping tumour heterogeneity we will develop FGS probes which can identify particular subgroups of the tumour (for example, more aggressive areas). Multiple probes will also overcome some of the known issues with tumour heterogeneity and downregulation of targets. These probes would allow surgeons to better tumour intra-operatively and improve outcomes.