Testing new gene therapies more efficiently

A research team headed by Janine Reichenbach, Professor of Paediatric Immunology and Co-head of the Division of Immunology at the University Children’s Hospital Zurich (UZH), has developed a new cellular model that enables much more efficient testing of the efficacy of new gene therapies. The team’s work, published in the March 2017 edition of the journal Scientific Reports, in an article entitled ‘CRISPR/Cas9-generated p47phox-deficient cell line for Chronic Granulomatous Disease gene therapy vector development’, acknowledged the support of the CGD Society in helping to fund the work.

Better cell model developed thanks to ‘gene scissors’

‘We used Crispr/Cas9 technology, so-called “gene scissors”, to change a human cell line so that the blood cells show the genetic change typical of the p47phox form of CGD, explains the paediatrician and immunologist. In this way, the modified cells reflect the disease genetically and functionally. Until now, scientists had to rely on using patients’ skin cells that they had reprogrammed into stem cells in the lab. This approach is laborious, and requires considerable time and money. ‘With our new testing system, this process is faster and cheaper, enabling us to develop new gene therapies for affected patients more efficiently’, says Janine Reichenbach.

Already about ten years ago, the team of Janine Reichenbach initiated the first worldwide clinically successful gene therapy study for the treatment of children with CGD – headed at that time by UZH’s now emeritus Professor Reinhard Seeger. The principle was to isolate blood-forming stem cells from the patient’s bone marrow, transfer a healthy copy of the diseased gene into these cells in the lab and then infuse the gene-corrected cells back into the blood of the patient. The corrected blood stem cells find their way back to the bone marrow where they engraft and produce healthy immune cells.

New ‘gene ferries’ make gene therapy safer

To transfer the healthy copy of the gene into diseased cells, until now modified artificial viruses have been used as a transport vehicle for the correcting genes. Despite curing the primary disease, gene therapies using first generation retroviral gene correction systems are now outdated, owing to the development of malignant cancer cells in some patients in European studies. Janine Reichenbach’s team works with a new improved ‘gene ferry’. ‘Today, we use so-called lentiviral self-inactivating gene therapy systems that are efficient and, above all, work more safely.’ UZH is one of three European centres able to use this new gene therapy in an international clinical phase I/II study to treat children with CGD (EU-FP7 program NET4CGD).

The future of gene therapy: precise repair of defective genes

For Janine Reichenbach’s team, such new ‘gene ferries’ are only an intermediate step. In future, gene defects shall no longer be treated by adding a functioning gene using viral ‘gene ferries’, but instead will likely be repaired with pinpoint precision using genome editing. Crispr/Cas9 is key here too. ‘Support by the CGD Society triggered the development of the new cell model which now allows for testing of present viral gene ferries as well as future non-viral gene ferries and gene correction approaches.’

However, it will be another five to six years until this ‘precision gene surgery’ is ready for clinical application. Janine Reichenbach appears optimistic. ‘Within the framework of UZH, we have the technical, scientific and medical know-how on site to develop new therapies for patients with severe hereditary diseases faster and establish UZH as an international competence centre of excellence for gene and cell therapies in the future.’

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