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Project Success Stories - Promising gene therapy for brain disease

Gene therapy could cure central nervous system diseases but currently no effective targeting mechanism can ensure that therapy reaches the right cells. European researchers are tackling this and other challenges to help combat degenerative diseases like Parkinson's. They are investigating avenues, such as viral vectors, to safely deliver gene therapy at the right location. Early breakthroughs look promising.


Central nervous system (CNS) diseases are among the most devastating and destructive conditions affecting both the patient and ultimately their loved ones. Parkinson's disease, for example, is a degenerative disorder that slowly erodes motor skills, cognitive processes and other brain functions, causing sleep and sensory difficulties. Physically, patients typically experience tremors and their movements become slower and more careful, while their posture can become rigid and less stable. There are cognitive and neurobehavioral impacts as well, such as dementia which can affect attention, language, problem-solving and memory, turning loved ones into strangers. 'Curative therapies still do not exist for most CNS diseases, but gene therapy is a promising new approach,' says Dr Sebastian Kügler, a senior researcher with the Neugene project. 'We believe that it is possible to modify brain function and pathophysiology by targeted delivery of specific curative factors to selected populations of brain cells that are affected by disease,' he says. Gene therapy is an exciting and rapidly developing branch of medicine that treats disease by inserting, altering or removing genes from within an individual's cells and biological tissues. The most typical application of gene therapy replaces mutated genes with normally functioning ones. New genes are inserted using viral vectors, which enter the target cell and deliver their genetic payload, and then the viral particles are degraded. The technology is still in its infancy, but there have been some partial successes, most notably in the treatment of severe combined immunodeficiency (SCID), the 'bubble boy' disease, where a child's immune system is so severely compromised that he or she must live in a sterile environment. Popular awareness of SCID came thanks to the 1976 film The boy in the plastic bubble, which starred a young John Travolta, and was based on the story of David Vetter who spent his short life inside a sterile bubble. Science has progressed in the 25 years since the film, but there are still open questions. Eight out of nine male infants born with SCID were still alive and well nine years after they underwent gene therapy in France. But there were associated risks: almost half of the participants in the study developed acute leukaemia after the therapy. Three survived, while one died. More work needed Clearly, more work needs to be done but gene therapy remains a potentially powerful approach to the treatment of many diseases. 'It opens the door for effective treatment regimes for CNS diseases, too,' notes Dr Kügler. 'It can be tailored to individual patients' needs. However, currently available gene transfer vectors have limitations regarding safety and efficacy, as they do not allow for targeting of specific populations of neurons or glia, or regulation of transgene expression.' Glia are brain cells that provide support and protection for neurons, and regulation of transgene expression is important because scientists want to know reliably how a transferred gene will be expressed, or activated, and they want to control, or regulate, the process. Overcoming these limitations is a key goal of the Neugene consortium, which gathered European scientists from academia and industry. The consortium is developing tools based on Adeno-associated viruses (AAV) and Lentiviruses (LV) for targeted and regulated gene transfer into different populations of CNS cells. Adeno-associated and Lentiviruses are commonly occurring types of virus but those used for therapy are not disease carrying. The consortium is developing a selection of vectors which are optimised for different therapeutic approaches. For example, one approach is to regulate the expression of neurotrophic factors, a collection of proteins that influence the growth and survival of developing neurons and the maintenance of mature ones. Another approach that Neugene is developing will target the manipulation of neurotransmitter synthesis in specific neurons. Neurotransmitters are the chemical stimulants that transmit signals across the brain. Neugene is working on several related goals. It is developing vectors to target specific cell populations, methods to tightly control the expression levels of therapeutic genes, and safety measures using a well-established animal model for Parkinson's disease. Final stretch Neugene is in the final stretch of a three-year project and work has progressed well. It achieved a major success by developing a virus that targets astrocytes. Astrocytes are star-shaped glia cells that provide many functions including support, nutrition, scarring and repair of various brain cells. 'Functionality of the brain depends by no means on neurons only. Glial cells and especially astrocytes serve essential roles,' explains Dr Kügler. 'Making brain astrocytes available for CNS gene transfer strategies was one major focus of Neugene, and it has been fully achieved ahead of schedule.' Doctors will ultimately be able to target these important cells thanks to the work of Neugene, and it is considered a breakthrough. 'Moreover, we optimised gene transfer into the main target cell population affected by Parkinson's disease,' stresses Dr Kügler. The study of transgene expression regulation has advanced well, too. Here the project pursued two potential regulation systems, one using regulatory proteins and another using ribonucleic acid (RNA) aptamers. Aptamers bind to specific target molecules. Protein-based regulation is showing excellent progress and is being tested on the animal models. 'The RNA aptamer strategy is completely novel and represents a high-risk/high-gain project, and considerable progress has been made in assembling the assay system necessary for identifying suitable aptamers,' Dr Kügler notes. The consortium has also developed a functional module for validating its work, including dosage optimisation for some of the team's viral vectors. The impacts of this research could be far-reaching. 'The socio-economic burden of diseases affecting the human central nervous system is estimated [at] 35 % of all EU disease burden,' reveals Dr Kügler. 'Demographic changes in ageing societies of the EU will increase this rate considerably and this will represent a crucial challenge to forthcoming generations,' he suggests. This makes Neugene's work on advanced gene transfer vectors and tools to implement safer, more efficient therapeutic options against Parkinson's and other severe CNS disorders both timely and important. The Neugene project received funding from the Health programme of the EU's Seventh Framework Programme for research.