First results gene therapy for frontotemporal degeneration are promising

14 May 2024
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For the first time, a form of gene therapy was tested in patients with hereditary frontotemporal degeneration (FTD) due to a progranulin mutation. The initial results, published in the journal Nature Medicine, show that the treatment is safe and succeeds in restoring reduced levels of the progranulin protein in this brain disease. Further clinical studies will assess whether the treatment also has a positive effect on the evolution of the clinical symptoms. 

Frontotemporal degeneration (FTD) is a rare brain disorder that goes together with drastic behavioural changes, personality and language. The disorder can occur from the age of 45 onwards, and leads to a loss of independence and is untreatable today. After years, FTD has a fatal outcome.  

Gene therapy with healthy progranulin

In some patients, FTD is caused by a mutation in the gene for progranulin, a protein hat, among other things, plays a role as an anti-inflammatory and growth factor for brain cells. As a result of that genetic defect, the level of functional progranulin is only half as high in those patients. 

This deficiency can be restored by administering the genetic code of healthy progranulin in the cerebrospinal fluid in order to reach the brains. The piece of DNA is encased in a harmless viral vector (AAV9) and taken up by brain cells in the nucleus, but does not settle into its own genetic material. This so-called gene replacement therapy for FTD has now been tested for the first time in humans in an international clinical trial. The phase 1-2 study primarily investigated the safety of the treatment and its efficacy in raising progranulin levels. 

Prof. dr. Rik Vandenberghe, neurologist and head of the memory clinic at UZ Leuven, collaborated on this. “Our initital results show that progranulin gene therapy is feasible and that risk of side effect is controllable. Both six and twelve months after one single administration, the amount of granulin in the cerebrospinal fluid and the patients' blood was restored to normal levels. These findings are very promising and are the basis for a follow-up study in a larger group of patients with FTD, which has already been started.”

Our first results show that progranulin gene therapy is feasible and that the risk of side effects is manageable.
Prof. dr. Rik Vandenberghe

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UZ Leuven is one of the three study centres worldwide that take part in this first clinical trial sponsored by the company Prevail Therapeutics (Eli Lilly). The specific drug is known as PR006.

Prof. dr. Vandenberghe: “These types of studies are only possible thanks to patients and relatives who are prepared to collaborate. We want to thank them explicitly. The rarity of the disease makes it a challenge to find sufficient study participants and underlines the crucial importancen of networks and reference centre for rare diseases, such as hereditary types of FTD, also in Flanders.”

Testing the new treatment at UZ Leuven was made possible thanks to an interdisciplinary collaboration between the different disciplines and their unique expertise, more specifically the hospital pharmacy, phase 1 unit (prof. dr. Jan de Hoon), interventional radiology (prof. dr. Philippe Demaerel), anaesthesia (prof. dr. Frederik De Buck), nephrology (prof. dr. Dirk Kuypers), the FTLD clinic (prof. dr. Mathieu Vandenbulcke and prof. dr. Rik Vandenberghe) and the clinical trial unit of the memory clinic (Carine Schildermans, prof. dr. Rik Vandenberghe).

Last edit: 17 July 2024