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A new improved gene therapy can be the first treatment for Machado-Joseph disease

* Gabinete de Planeamento, Estratégia, Avaliação e Relações Internacionais / Ministério da Ciência, Tecnologia e Ensino Superior

Portuguese, Swiss and French researchers show, for the first time, that is possible to inhibit, in a living organism, the mutated copies of a gene without affecting any existing normal copies of the same gene. The research, to appear in the 8th of October edition of the journal PLoS One, describes how scientists successfully used the approach in rats to reverse the symptoms of Machado Joseph Disease (MJD), an untreatable and potentially fatal neurodegenerative disease.

If these results can be transferred to humans – and the method is shown to work on isolated human cells - it can, not only become the first available treatment for MJD, but also open the door to promising new safer and more efficient gene therapy for other neurodegenerative disorders, such as Alzheimer’s or Parkinson’s disease.

MJD (or spinocerebellar ataxia type 3) is a neurodegenerative disease provoked by the abnormal repetition of a set of three nucleotides – nucleotides are the DNA building blocks - within the MJD1 gene, which produces the brain protein ataxin-3. The mutated protein, incapable of functioning normally, accumulated instead as insoluble deposits in the patients’ brain, promoting the neural damage linked to the disease. MJD is characterised by high motor discoordination and progressive lack of motor control leading to wheelchair confinement and, in extreme cases, death. The disease is also untreatable.

Sandro Alves, Luís Pereira de Almeida, Nicole Déglon and colleagues from the Center for Neurosciences & Cell Biology and the Faculty of Pharmacy at the University of Coimbra, Portugal and the Institute of Molecular Imaging and Molecular Imaging Research Center in Orsay, France have been interested for a long time in neurodegenerative disorders, particularly MJD, and in the research now published exploit a powerful new tool called RNA interference (RNAi) to try and silence the mutated MJD1 and control the neural damage associated with the disease. The method is based on the fact that during gene expression, the information contained in the DNA is transferred to molecules of messenger RNA (mRNA) that then instructs other molecules to produce a protein. The RNAi method introduces, into the cells expressing the gene we want to silence, a molecule of RNAi complementary to this gene mRNA, so the two molecules will bind together. Since two RNA molecules do not exist naturally, this double RNA will be quickly eliminated stopping gene expression half way (thus the name “RNA interference”).

What is particularly new and interesting about Alves, Almeida, Déglon and colleagues’ work is that they use a RNAi that specifically targets the mutated version of the ataxin-3 gene, without touching any normal MJD1 still existent in the cells. In fact, there are always two copies of any gene in any cell, what means that most of the times MJD patients – because one mutated MJD1 is enough to produce the disease - still have one functional copy producing ataxin-3. This new RNAi targets a very small region in the MJD1 mRNA found to be different between the normal and mutated versions of the gene. As ataxin-3 is believed to participate in the destruction of abnormal and potentially toxic proteins in the brain, exactly the same ones that can lead to neurodegenerative diseases, it is important to protect whatever production of this protein might still exist.

With this new RNAi in hands the researchers started by assessing its effectiveness on isolated human embryonic kidney cells where it was shown to eliminate mutated MJD1 mRNA leading to as much as 70% reduction in the levels of abnormal ataxin-3.

Next, the RNAi was used on a MJD rat model developed by the researchers and where the disease was created by injecting a virus containing a mutated human MJD1 gene into the animals’ brain. As the animal’ brain cells became infected – and since these viruses infect by inserting themselves into the host chromosomes, in this case taking also the mutated MJD1 – , they produce mutated ataxin-3 and, this way, create a MJD-like disease. In this new experiment, the animals were injected not only with the virus containing the mutant human MJD1 but also with one containing the RNAi, so that this last molecule could interfere in the brain cells’ production of abnormal ataxin-3. And in fact, three weeks after the injections, analysis of the rats’ brain revealed a substantial reduction in both the number and size of (abnormal) protein deposits (50% reduction) and neuronal damage (70% reduction) in comparison with controls, demonstrating the capacity of this protocol to control MJD in live organisms. Although this RNAi has been previously shown by others to silence the mutated MJD1 in isolated cells, Alves and colleagues manage to deliver it into the organisms’ brain achieving, for the first time, a mutation-specific gene therapy in live animals.

Further research needs to be done to assure the method’s safety and long-term results before it can be used in humans but the fact that it is possible to silence mutant human ataxin-3 production in rats’ brain is very promising. Furthermore, both the treatment of live animals and of isolated human cells, showed no apparent side effects, a crucial characteristic to be used in humans. One of the biggest worries of this kind of methods is the introduction of a virus in the body that, although innocuous when injected, always has the (remote) potential to mutate into a disease-inducing form, or – like it happened a few years ago in human trials of gene therapy – activate cancerous genes. Nevertheless, a viral system similar to the one employed by Alves and collaborators is now being used on a human trial of gene therapy for Parkinson’s with no side effects, further supporting the relevance of the results here described to eventual human treatments.

And in fact Luis Pereira de Almeida one of the authors says “the next immediate step is to use a transgenic mouse model, where the animal expresses in most brain cells the mutated ataxin-3 a situation much closer to what happens in patients, to validate the silencing approach and better predict the outcome of a clinical treatment within specific regions of the brain. If these studies are successful, next we will try to attract the interest of pharmaceutical companies working in this area to bring therapy to clinical trials”

Finally the research has one further implication. After all, this is the first time that it is possible to silence the production of a mutated protein without affecting any normal versions of the same protein in the brain of live animals. With the increasing use of gene therapy now been seen, particularly RNAi in the treatment of neurodegenerative diseases, to be able to save any normal protein production is a major advantage, especially in an organ like the brain. Alves, Almeida, Déglon and colleagues show how this is possible opening the door to safer and more specific RNAi gene therapies.

MJD has first been detected in Portuguese/Azorean descents in the 1970s (Machado and Joseph are the surname of the two Portuguese families first affected identified) but it is now spread throughout the world where it is the most common ataxia (neurodegenerative diseases characterised by high motor discoordination). Nevertheless, the Azorean island of Flores is still the place with highest incidence of the disease with an incredible 1 in 140 people affected by it. Symptoms include increasing limb weakness (ataxia means motor discoordination) and widespread clumsiness, speech difficulty and a progressive loss of general motor control that eventually confines the patient to a wheelchair and, in most severe cases, leads to premature death.

Piece by Catarina Amorim (catarina.amorim at

Catarina Amorim | alfa
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