Poyraz was still very small when he was diagnosed with ataxia teleangiectasia - a rare genetic disease that affects the nervous system and increasingly limits motor skills in particular - from walking and standing to fine motor skills, speech and swallowing. The disease makes him walk unsteadily, but also makes him susceptible to infections and reduces his life expectancy. The diagnosis came as a shock to Poyraz's parents. The average life expectancy of those affected is around 20 to 30 years, with many dying from lung infections or cancer - or from increasing immobility and bedriddenness due to the loss of motor skills. But then Poyraz's parents found out about Professor Matthis Synofzik and his team at Tübingen University Hospital. The neurologist specializes in the research and treatment of rare neurodegenerative diseases. One of his pioneering research areas is the development and testing of personalized RNA therapies. For patients like Poyraz, this means a glimmer of hope: a tailored therapy that specifically targets very individual gene mutations such as those in Poyraz's case, possibly slowing down or even stopping the progression of his disease.
Precision medicine in neurology
The research approach: individually tailored RNA-based therapies
Matthis Synofzik works at the interface between clinical practice and research, with the aim of gaining a better understanding of genetic diseases. RNA therapy is a relatively new form of treatment that aims to alter genetic information at the RNA level. Together with international colleagues, Professor Synofzik is developing a form of RNA therapy - known as antisense oligonucleotide (ASO) therapy - which they can tailor to the individual genetic alterations of individual patients. “This therapy uses synthetic RNA molecules that bind specifically to the faulty RNA in the nervous system,” explains Synofzik. “In this way, the affected gene segment can be stabilized, the protein restored and the disease process possibly slowed down.” In the case of Poyraz, international colleagues with whom Matthis Synofzik works closely had coincidentally just developed an ASO that matched the genetic alteration in Poyraz. Thanks to the translational structure “from bench to bedside” implemented in parallel by Matthis Synofzik, i.e. from the laboratory to the clinic, this treatment could be translated directly into clinical treatment on site.
However, the path to developing such a therapy is anything but simple. First of all, Synofzik's team has to identify the exact genetic errors that cause diseases such as Poyraz's in individual patients. To do this, they analyzed the genes of those affected and compared them with the few known cases worldwide. In Poyraz's case, they discovered that the cause of the disease lies in mutations in the ATM gene, which is normally responsible for DNA repair. The team is therefore designing customized RNA molecules (i.e. ASOs) that are precisely tailored to the individual, very personal mutations - as in Poyraz. “We have to find the individual key for the door lock of every patient,” says the neurologist. A time-consuming process that required both time and resources - and all with an uncertain outcome. In Poyraz's case, this was achieved very quickly: although none of the many ASOs that Synofzik's team has now developed for gene mutations in individual patients matched, an ASO from a collaboration partner from Professor Synofzik's close international cooperation did.
From research to application
The development of such an RNA therapy is often like a race against time, especially for young patients like Poyraz. “Time is brain,” says Professor Synofzik. “The earlier we treat, the more effective the therapies are.” Professor Synofzik and his team are doing everything they can to bring innovative approaches to the clinic as quickly as possible, without neglecting safety standards. After the ASO therapy was tested on models and classified as safe, cautious clinical application began with Poyraz. Will the therapy be effective? Neurologist Synofzik will not be able to say for several years. To date, however, Poyraz has hardly any further symptoms, so the disease is probably stagnating. Is this just the natural individual course of the disease - or is it actually a successful therapy? Only time will tell.
The platform approach: from therapy for one individual to therapy for many individuals
But the findings should not just be reserved for the seven-year-old boy. He is just the first example of a much more comprehensive underlying approach. According to the principle of “n-of-1 for n-of-many”, Professor Synofzik's therapy development is embedded in a more comprehensive platform approach. The personalized treatment for a first individual patient (n-of-1) is only the forerunner for an entire underlying platform development, where the individual therapies, if successful, are then applied to other patients with genetic mutations of a similar type, but completely different neurological diseases (n-of-1 for n-of-many).
Synofzik, together with national and international colleagues from the “1 Mutation 1 Medicine” (1M1M) network, has now embedded this platform approach in a more comprehensive care and networking process so that other doctors and their patients can also benefit from the platform approach. They provide a kind of “template” that supports doctors throughout Europe with valuable information and therapeutic approaches when they encounter patients with similar rare genetic mutations.
The work of Professor Synofzik and his team has far-reaching implications for the treatment of rare genetic diseases. Their research shows that it is possible to develop an individually tailored therapy for each patient - a kind of “customized medicine” that could shape the future of neurology. By combining cutting-edge technology with a deep understanding of the genetic basis of these diseases, Synofzik and his team are thus creating new perspectives for people like Poyraz, but at the same time a whole new direction in neurology: individually tailored precision medicine.
