MHH scientist Professor Axel Schambach has been awarded the coveted Proof of Concept Grant for the second time for his pioneering research into Usher syndrome. He wants to insert a healthy copy of the defective gene directly into the eye to prevent impending blindness.
With Usher syndrome, this may soon be a reality: a cure via gene taxi.Copyright: pixabay, Karin Kaiser/MHH
There are various hereditary causes of vision loss. A particularly severe form is Usher syndrome type 1B (USH1B). In addition to gradual loss of vision, those affected also suffer from severe deafness and balance disorders. This is caused by a mutation in a gene called MYO7A. If a person inherits the damaged gene from both their father and mother, no healthy variant can compensate for this deficiency and the disease develops. Professor Dr Axel Schambach, head of the Institute for Experimental Haematology at Hannover Medical School (MHH), wants to use gene therapy to protect those affected from the consequences of this gene mutation. He has already received one of the European Union's highest grants for scientific excellence for this work. His research project iHEAR was awarded the coveted Consolidator Grant by the European Research Council (ERC). In the subsequent Proof of Concept (POC) project MY-O-SENSES, his research team and its partners succeeded in introducing intact copies of the damaged gene into the inner ear, where they were able to at least partially correct the hearing and balance disorders. The new EuroVision project has now also received PoC funding and aims to extend the successful gene therapy to the eye.
Gene taxi delivers intact copy to destination
Sight is our most valuable sense, followed by hearing and balance. More than 200 million people worldwide are affected by moderate to severe visual impairment, and an estimated 43 million people are blind. So-called monogenic diseases, which are caused by mutations in a single gene – such as MYO7A – are responsible for the loss of vision in more than two million people. ‘Current treatment options for genetic vision loss are limited,’ says Professor Schambach. There is therefore a high clinical need for innovative approaches such as gene therapy. In the EuroVision project, the researchers want to tackle the causes directly and deliver a healthy version of the MYO7A gene directly to the retina, where the sensory cells responsible for processing light stimuli are located. This is done using a viral vector, colloquially known as a gene taxi. ‘Since MYO7A is a very large gene, we need a gene taxi with a large trunk, so to speak,’ explains the molecular medicine expert. The research team therefore uses lentiviral vectors (LV), which can carry a large amount of genetic material without losing any along the way. The LV system was developed in the iHEAR project and improved in the MY-O-SENSES project to make it as safe and effective as possible. The gene taxi is administered into the eye via microinjection and is designed to deliver the therapeutic gene precisely to the retina, which lines the inside of the eye like wallpaper.
Application in the eye is more complicated
Although the light receptors in the eye behave similarly to the hair cells in the inner ear, which are responsible for sound perception and position detection, the application of the lentiviral vector in the eye is more complicated. ‘In the inner ear, the sensory cells are directly adjacent to fluid, so we were able to inject our gene taxi there,’ says Dr. Juliane Schott, who has already worked on gene therapy in the iHEAR team. ‘In the eye, on the other hand, there are many interconnected sensory cells and barriers in between that we have to overcome somehow.’ The researchers therefore still need to verify whether the vector actually delivers its cargo to the desired target.
Groundbreaking therapy
‘However, we will soon be able to manufacture our gene taxi in GMP production, i.e. in accordance with the strict quality standards and guidelines for medicinal products and medical devices monitored by the state,’ emphasises Professor Dr Michael Morgan, also from the iHEAR team. The application in the eye is now being investigated in a mouse model. Once preclinical development has been successfully completed, the medical product must still be approved by the relevant authorities. The gene therapy can then be tested in clinical trials to determine its safety and efficacy in humans. The research team is confident that the end result will be a successful LV gene therapy for the treatment of USH1B. ‘The EuroVision product will be the first and only single-vector treatment for vision loss caused by MYO7A mutations,’ emphasises Professor Schambach. ‘This groundbreaking therapy has great potential to significantly improve the quality of life of those affected and will form the basis for the treatment of other monogenic eye diseases that require the transfer of large genes and for which there is an urgent medical need.’
The EuroVision project is a collaboration between the MHH Institute for Experimental Haematology, the Institute of Developmental Biology and Neurobiology and the Institute of Zoology at Johannes Gutenberg University Mainz, the Department of Ophthalmology at Ludwig Maximilian University Munich and the Institute of Animal Physiology and Genetics at the Czech Academy of Sciences.
The European Research Council's Proof of Concept (PoC) funding line supports scientific projects for 18 months with a grant of €150,000. It is aimed exclusively at researchers who already hold an ERC grant and wish to further develop a research result from their ongoing or completed project beyond the scope of research. However, the PoC is not a continuation of the research of the actual ERC project. Rather, it serves to explore its commercial or societal potential – a first step towards transferring the research results into clinical practice.
Text: Kirsten Pötzke