Community Research and Development Information Service - CORDIS


GTNCTV Report Summary

Project ID: 294745
Funded under: FP7-IDEAS-ERC
Country: United Kingdom

Final Report Summary - GTNCTV (Gene therapy and nanotechnology based CNS targeted vectors)

Motor neuron diseases are a group of devastating conditions. Examples of these conditions include amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). SMA, an inherited condition affecting children, is due to premature loss of motor neurons resulting in progressive paralysis. Motor neurons are nerve cells that send messages from the spinal cord to muscles to stimulate contraction. 50% of affected children die by the age of 2 years. Motor neuron injury is caused by deficiency of the SMN protein. We have restored the SMN gene into cells using virus carriers modified to remove all their harmful properties, making them safe for human use. We successfully used our approach to restore the level of SMN protein in both skin cells donated by an SMA child, and in a mouse model of SMA leading to markedly increased survival in the animals. These results have generated great optimism among patients and their families. However, further studies are needed to overcome difficulties preventing development of effective therapies for these conditions: i) poor understanding of why motor neurons die in SMA and ALS; ii) lack of efficient way of delivering treatment at therapeutic levels to the brain and spinal cord; iii) the need to refine our strategy by improving the specificity of the therapeutic virus carrier to neurons within the brain and spinal cord.

Our aims are to: 1) understand how our virus carrier enters the brain and spinal cord when administered in the blood; 2) refine the specificity of the virus carrier for neuronal cells, which would help prevent potential adverse effects because of the potential off-target effects of gene expression within vital organs such as heart and liver; 3) generate models of the disease and study how motor neurons die; and 4) test new therapies for motor neuron diseases.

Several achievements emerged from our ERC programme are: a) developed and characterised an in vitro blood-brain barrier model comprising porcine brain endothelial cells and primary mouse astrocytes, which form tight junctions, can be transduced with the virus carrier, and allowed us to identify the receptors mediating entry of the viral carrier into the CNS; b) to track the migration of the viral particles in vitro and in vivo, we have developed a novel site-specific labelling system that exploits the chemistry of thiol-conjugated reactions to generate a fluorescently labelled AAV9 virus carrier; c) we have also utilised this modified viral carrier to identify proteins interacting with the viral carrier through biotin-streptavidin complex formation in the brain; d) we refined the specificity of our virus carrier to target cells within the CNS by introduction of neuronal promoters; e) we successfully created hybrid vectors using nanoparticles and the virus carrier; and f) we have developed virus carriers that can be used to create models of SMA and ALS; g) used these models to study the mechanism of disease and generate exciting discoveries; h) finally, test novel therapies.

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United Kingdom
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