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14 April 2014

Generoso Andria – Enzyme and gene therapy for treating genetic disorders

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Genetic malfunctioning of waste recycling in the cell causes serious disorders. Enzyme replacement therapy proves effective and gene therapy looks promising

Lysosomes are intracellular organelles that degrade and recycle ‘waste’ molecules. Lysosomal Storage Disorders (LSDs) comprise a large group of congenital metabolic diseases affecting altogether one in 8,000 newborns. These conditions arise from lysosomal enzymes malfunction that cause the accumulation of harmful ‘waste’ molecules in the cell. Usually LSDs are multi-systemic disorders and in frequent case they affect also the central nervous system they are called neuronopathic.

The EU-funded EUCLYD project, completed in 2011, studied four non-neuronopathic LSDs that are affecting various organs, namely diseases such as Gaucher and Pompe disease, and mucopolysaccharidosis VI (MPS VI). Project coordinator Generoso Andria, professor of paediatrics at the University Federico II in Naples, Italy, talks to about enzyme replacement therapy and gene therapy that have been emerging since the completion of the project.

How do we recognise a LSD?
Most LSDs are autosomal recessive—meaning you need two copies of the defective gene for the disease to develop. There is a wide and continuous range of manifestations of these genetic diseases. This is what makes them very difficult to treat. First of all, a disease caused by the same defect does not manifest itself in the same way in patients. It depends on where the mutation on the gene is and on how functional the enzyme is. Sometimes, the enzyme is produced, but is not stable, and it is degraded before reaching the lysosome. In other cases, the enzyme can function partially. The same disease has child, young and adult forms.

Why was it useful to focus on non-neuronopathic LSDs using enzyme replacement therapy?
One of the goals of the project was to study therapeutic strategies for these diseases. We have been using enzyme replacement therapy for some years. This approach consists of artificially synthesizing the enzyme with the malfunction and administering patients the correct copy through an injection every seven to 15 days. Most lysosomal enzymes have a ‘tag’, like the luggage in an airport. And like a suitcase, it goes straight to its destination, namely the lysosome, where it can execute its function.

But in the brain we have a defence system called the blood-brain barrier, which prevents large molecules, like these enzymes, from entering. One of the limitations of enzyme replacement therapy is that the enzymes do not reach the central nervous system. So this approach can improve the situation of other organs affected by the disease, such as the spleen or the liver, but it does not cure compromised neurons. By focusing only on diseases not affecting the brain, we had more freedom to test new therapeutic strategies.  

Previously, it worked amazingly well for Gaucher Disease, a disease affecting the white cells, where a lipid accumulates. The therapy received the green light very quickly from the US drug regulatory agency FDA. But not in all LSDs the enzyme replacement therapy works so effectively, and it is not yet clear why.

What other therapeutic approaches have you tested?
For MPS VI, which affects the skeletal system, Alberto Auricchio at the TIGEM Institute—the Telethon Institute Of Genetics And Medicine, in Naples, Italy—prepared a viral vector that could insert the normal gene directly in the affected chromosome. We have started testing this gene therapy for toxicity, and we plan to recruit patients in 2014-2015. Enzyme replacement therapy for MPS VI is also available, but needs to be administered every seven days and the results are variable. On the other hand, gene therapy would have to be administered only once in a lifetime. The vector has a tropism to the liver, meaning it tends to accumulate there. And once the liver cells ‘swallow’ the new gene, they maintain it permanently and produce the new enzyme for all cells in the body.

Were there any other important results found by the project consortium?
Andrea Ballabio, at the TIGEM institute, made an important discovery. All lysosomal enzymes are under a master regulatory gene, called TFEB, a gene that modulates the enzyme activity. This system has other functions related to the energy system of the cell; so it knows when cells need nutrients. It also intervenes in a process called exocytosis, which is the expulsion of material from the cell. This could provide a new strategy to work on in the future to help the cell free itself from the accumulation of the substances caused by LSDs. provides its content to all media free of charge. We would appreciate if you could acknowledge as the source of the content.