NEUGENE

Advanced gene therapy tools for treatment of CNS-specific disorders

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 Obiettivo del progetto (Objective)

'Curative therapies still do not exist for most CNS diseases but gene therapy is a promising new approach. We propose that it will be 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. This opens the door for effective treatment regimes, which 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. The NEUGENE consortium has been founded by leading European scientists from academia and industry to overcome these limitations. The consortium will develop Adeno-associated virus (AAV) and Lentivirus (LV)- based tools for targeted and regulated gene transfer into different populations of CNS cells. The consortium will provide a selection of vectors that are optimized for different therapeutic approaches, e.g. regulated expression of neurotrophic factors or manipulation of neurotransmitter synthesis in specific neurons. NEUGENE has three major goals:1) targeting gene transfer vectors to specific populations of neurons and glia, by transcriptional regulation and miRNA-mediated de-targeting and by exploiting the cell-specific tropism of novel types of viral vectors, 2) tight control over expression levels of therapeutic genes by using regulated systems based on different principles, and 3) establishing the safety of the novel vector tools. NEUGENE will verify the functional efficacy of the novel CNS gene transfer tools in a well-established animal model of Parkinson's Disease (PD). This disorder affects over 1.000.000 Europeans and is increasing in prevalence with the aging population. Importantly, principles and mechanisms developed and evaluated within the consortium will also be of direct relevance for gene therapy of many other brain disorder.'

Introduzione (Teaser)

Gene therapy entails the specific transfer of genetic information into affected cells and tissues in order to restore function in diseased areas. European scientists aimed to apply this approach to neurological disorders where no alternative treatments are available.

Descrizione progetto (Article)

Great progress has been made over the last decade in understanding mechanisms and principles of both normal brain function and central nervous system (CNS) disorders. Although this information makes new treatments for nervous system diseases more realistic, current pharmacological treatment strategies for neurodegenerative diseases offer only symptomatic relief and cannot influence the course of the disease.

Although still an experimental approach, gene therapy presents a promising strategy for permanently correcting a genetic phenotype. Several proteins and regulatory RNAs have been identified to regulate normal brain function and affect disease progression. Targeting these molecules directly through gene therapy may be more time- and cost-effective compared to medications developed through classical pharmacology.

Seeking to treat major neurodegenerative disorders, the EU-funded 'Advanced gene therapy tools for treatment of CNS-specific disorders' (Neugene) initiative worked to overcome existing limitations of current gene therapy vectors for safe and efficient approaches. The consortium used Parkinson's disease as a model with a goal to target viral vectors to specific cell types of the brain and achieve regulated, efficient and safe expression of therapeutic molecules in either neurons or glia.

Vectors based on adeno-associated virus (AAV) and lentivirus (LV) were developed that specifically delivered therapeutic genes to astrocytes and to the main target cell population affected by Parkinson's disease. Through specific promoters and regulatory protein-based approaches, partners achieved targeted transgene expression.

With respect to safety of the developed vectors, the consortium showed that existing immunity towards AAV serotype 2 could compromise the efficiency of transfer and transgene expression. The use of alternative vectors based on equine infectious anaemia virus (EIAV), to which humans are not naturally immunocompetent, argued for a superior safety profile.

Neugene vectors were functionally validated in a mouse model for Parkinson's disease, demonstrating restoration of motor performance. Also, neurotrophin-expressing vectors were patented and put forward for clinical development.

Overall, the Neugene research solved significant issues regarding the gene therapy of CNS disorders. The newly developed vectors boasted efficient yet cell-restricted and regulated transgene expression, setting the basis for gene therapy for CNS disorders.