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New study shows potential of gene therapy in nephrotic syndrome

10 August 2023

In a new study published in Science Translational Medicine, researchers at the University of Bristol have shown that just one dose of gene therapy targeting cells in the kidney called podocytes has the potential to cure steroid-resistant nephrotic syndrome. 

An innovative approach for nephrotic syndrome

Nephrotic syndrome is a condition where the filtering units of the kidney are damaged, allowing large amounts of protein that should be kept in the bloodstream to leak into the urine. This can lead to swelling, particularly in the eyes and legs, and increased risk of infections and blood clots. It can occur at any age but is most commonly diagnosed in children under five years old. Often the symptoms can be managed with a type of medication known as steroids, however, around 10% of children with nephrotic syndrome do not respond to steroids and many will go on to develop kidney failure and will need dialysis or transplant within 2–5 years. 

In about one third of cases, this steroid-resistant form of nephrotic syndrome is caused by inherited (genetic) faults. The research team proposed that gene therapy could be applied to correct these faults. The most common fault is in one gene that codes for a protein called podocin, which is essential for the function of cells called podocytes (a critical part of the kidney’s filtration unit). 

With initial funding from Kidney Research UK in the form of a research fellowship award for lead author Dr Wen Ding, the Bristol team, led by Professor Moin Saleem and Professor Gavin Welsh, have been investigating whether replacing the faulty version of the podocin gene in patients with steroid-resistant nephrotic syndrome could cure the disease. 

Professor Moin Saleem, Dr Wen Ding and Professor Gavin Welsh (left to right)
Professor Moin Saleem, Dr Wen Ding and Professor Gavin Welsh (left to right)

Introducing gene therapy

Gene therapy is a technique which replaces or alters a faulty gene or adds a new gene to treat or prevent disease.  Diseases that result from a problem with a single gene are particularly good candidates for gene therapy. Cells like podocytes that are terminally differentiated (meaning that they are no longer able to divide) also make good targets for gene therapy as one treatment can last a lifetime. 

Restoring normal function in kidney cells

For gene therapy to be successful, researchers must make sure that the new genetic material reaches the right cells and is used by those cells for a long time to restore their normal function.

Moin explains: “The kidney is particularly difficult to target as there are so many different cell types and we need the new gene to produce podocin in the podocytes, but not the other kidney cells.” In this study, the team used a virus (which is incapable of causing disease but can deliver genetic information into cells) called adeno-associated virus (AAV) to deliver the podocin gene to the correct cell type alongside other DNA sequences which make sure it is only expressed in the podocytes.    

Using this technique, the team were able to replace the original faulty gene in the podocytes, successfully treating several different laboratory-based models of nephrotic syndrome. 

What could this mean for patients?

Further studies are now required to build upon these initial positive results and ensure that this approach is safe and effective for use in patients. 

“We are hoping that this treatment could be curative. You keep the same podocytes for life, so if you can change their gene expression right at the beginning of the disease, we should be able to prevent this disease from progressing. With most kidney diseases, there is a reasonable window of opportunity, often years, before you get irreversible damage to the kidneys, where we would hope to be able to intervene with gene therapy and avoid the need for dialysis or transplantation.” Moin Saleem

Dr Aisling McMahon, executive director of research and policy at Kidney Research UK said: “This work offers real hope for patients impacted by steroid-resistant nephrotic syndrome and potentially other genetic kidney diseases too. It is also a brilliant example of the importance of building capacity in renal research by funding early career researchers and we’re delighted to see that the work that Wen conducted during her fellowship has real potential to be used in the clinic.” 

A huge investment for kidney research

Moin has spent many years leading pioneering research into gene therapy for kidney disease and has recently founded the spin-out company Purespring Therapeutics to work towards treating kidney diseases by directly targeting the podocyte with AAV gene therapy. In 2020, Purespring Therapeutics secured a £45million investment from healthcare company Syncona Ltd - a much-needed investment into innovation of new therapies for kidney diseases as they move towards the clinic. 

What are podocytes? 

The filtering units of the kidneys are called glomeruli and they are made up of clusters of blood vessels and special cells called podocytes. Podocytes have finger-like arms which wrap around the blood vessels, acting like a filter to help prevent proteins and other large molecules from leaving the body. Podocin is a protein that is essential for maintaining this structure and preventing the filtering apparatus of the kidney from becoming too leaky.  

What is Gene therapy and how does it work? 

Gene therapy is a technique that can treat or prevent diseases that are caused by a fault in a gene (a change in the DNA sequence) by modifying a person’s genetic makeup. This could involve replacing the gene that isn’t working with a healthy copy of the gene, blocking a gene that is causing a problem, or introducing a new or modified gene into the body. Gene therapy has the potential to treat and cure a vast number of diseases including cancer, genetic diseases, and infectious diseases. 

There are a number of different ways to deliver a healthy copy of a gene into a cell. The team at Bristol are using a virus called adeno-associated virus (AAV), which does not cause disease but is able to deliver genetic material into cells. A section of DNA containing the instructions for making a protein (in this case, podocin) is packaged into the virus alongside other elements that make sure the protein is only produced in the correct cells in the body. The virus then carries the new DNA into the cells of the patient and once inside, the cell’s (in this case the podocyte) normal machinery produces a healthy version of the protein. 

Gene therapy using AAV is already being used in the clinic in the UK to treat the condition spinal muscular atrophy. 

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