Investigating the renal microvasculature in polycystic kidney disease

60,000 people in the UK have long term severe kidney disease. There is currently no cure and patients require dialysis or transplantation. One of the leading causes of long term kidney disease is polycystic kidneys. Our previous work has shown that one of the earliest events in the progressive decline of polycystic kidneys is changes in the small blood vessels of the kidney. Furthermore, we have shown that treatments using proteins which restore and stabilise these blood vessels improve disease progression. However, we do not yet fully understand how these treatments work. This will be investigated in this proposal by a team of scientists and clinicians based at the UCL Great Ormond Street Institute of Child Health and the University of Manchester using high resolution imaging, high-throughput sequencing technology and models which replicate polycystic kidney disease. These investigations will enhance our knowledge of how blood vessels are involved in kidney health and disease. Furthermore, if these studies are successful, it could be a new exciting therapeutic avenue for kidney patients in the future.

Aims and Objectives: Our aims will be to (i) determine whether gene therapy for VEGFC can treat a autosomal dominant PKD model; (ii) determine the mechanisms underlying VEGFC's effect in PKD.



Methodology: VEGFC will be administered in a model of autosomal dominant PKD by a gene therapy strategy using adeno-associated viruses. We will use a combination of histological and non-invasive imaging to assess the renal microvasculature. We will use transgenic technology to examine whether there are intrinsic defects in kidney endothelia in PKD. In addition, vascular cells lacking PKD genes will be isolated and their biology and gene expression (using RNA-sequencing) assessed. Finally, a 3-dimensional cell culture model will be used to examine if VEGFC directly modulates cystogenesis.



Scientific and Medical Opportunities: This project will enhance our knowledge of renal blood vessels in healthy and polycystic kidneys. In addition, it could lead to the design of new therapies for human renal disease. If this is the case then this will have potential impact on society by improving the quality of life of patients with kidney disease as well as a major economic impact by reducing the number of expensive dialysis regimens or the need for a kidney transplant.

This research has the potential to discover new treatment strategies for patients with PKD, which accounts for 10% of all cases of end-stage renal disease (ESRD). The UK prevalence of ESRD is 58,000 and every month 600 more people with chronic kidney disease reach ESRD. There is no cure for ESRD patients and they require life-long dialysis and transplantation significantly reducing their quality of life and placing a high burden on healthcare resources with current annual costs of the UK ESRD programme conservatively estimated to be £1 billion or 1% of the total National Health Service budget. Importantly, the therapeutic strategies outlined in this proposal could also be relevant for other renal conditions such as diabetic nephropathy which are also accompanied by changes in the renal microvasculature.

This proposal will take a novel approach and determine whether treatments that target kidney blood vessels can improve PKD. If successful, the work will provide compelling proof of concept evidence that vascular growth factors could be a new treatment strategy to improve this condition. This has the potential to impact on society by improving the quality of life of patients with kidney disease and have an economic impact by reducing the impact of ESRD and saving healthcare costs.

If manipulation of vascular growth factors proves to be a successful treatment for PKD, then this will be of clear interest to pharmaceutical companies. Many companies are interested in vascular growth factor therapy for other conditions and a large amount of compounds to manipulate these signalling pathways are available for therapeutic testing. With specific regard to VEGFC, Lymfactin, an adenovirus developed by Herantis Pharma based on VEGFC gene therapy has been approved in phase 1 clinical trials for breast cancer patients to ameliorate lymphoedema in upper limbs (http://herantis.com/pipeline/lymfactin-for-lymphedema/). Future strategies may involve drug screens to identify alternative modulators of the microvasculature which could be beneficial in PKD.

Importantly, Dr Long already holds a patent related to targeting the vasculature in PKD and with the help of UCL Business will have regular discussions with UK pharmaceutical companies to licence this intellectual property. If these studies develop new treatments for ESRD then this is likely to bring benefits to the UK economy.

The proposed research will also impact on researchers in multiple scientific disciplines including renal researchers, vascular biologists and immunologists. This is because it should provide insights into: (i) the renal microvasculature in healthy and polycystic kidneys; (ii) the investigation of vascular growth factors as a feasible treatment strategy for PKD (perhaps in combination with vasopressin receptor antagonists) (iii) how adeno-associated virus strategies can be used to treat renal conditions; and (iv) how vascular growth factors alter different cell types and effect downstream signalling pathways. In addition, new tools will be generated which will be of use to renal biologists, vascular scientists and immunologists. Finally, the investigators, post-doctoral researchers and collaborators on the application will directly benefit from the multi-disciplinary nature of the grant involving pre-clinical imaging, molecular and cell biology, gene therapy, transgenic animals and genomics (RNA-sequencing). Collaborators include Professor Mark Lythgoe (pre-clinical imaging), Professor Peter Harris, Professor Paul Beard (photoacuostic imaging) and Dr Simon Waddington (gene therapy).