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A novel gene therapy approach for treating Parkinson's disease

07/09/2017

Image of the whole brain treated with the virus expressing the GFP reporter
Image of the whole brain treated with the virus expressing the GFP reporter

Parkinson's disease is a progressive neurological disorder that affects people's movement abilities, and often results in symptoms such as tremors, slowed movements and muscle stiffness. In advanced stages, this disease might lead to cognitive, memory and psychiatric alterations as well that might be severely debilitating. A cardinal neuropathological hallmark of this disease are the Lewy bodies that are mainly constituted by the accumulation of a-synuclein in toxic aggregates within the neural cells that lead to dysfunctional neurons in large brain areas and the loss of the dopaminergic neurons. These harmful aggregates can be observed also in other related diseases known as parkinsonisms, such as multiple system atrophy, and in particular forms of senile dementia.

Parkinson’s disease and other parkinsonisms are affecting about 1% of the overall population above 60 years and, therefore, number of patients is expected to substantially upsurge with the increase in life expectancy. There are currently no treatments to stop the progression of the disease or to block the accumulation of the harmful a-synuclein aggregates.

Neuroscientists of the Institute of Neuroscience of the National Research Council and San Raffaele Hospital in Milan, Italy, have established the first approach worldwide of gene therapy to prevent and reduce accumulation of a-synuclein toxic aggregates to counteract the pathological progression of these diseases. Researchers have taken advantage of a new class of therapeutic viruses that once injected in the blood stream can easily penetrate the blood-brain barrier and spread throughout the brain. They equipped this virus to express the therapeutic gene GBA1, which is critical for degradation of toxic a-sinuclein aggregates. A single intravascular injection of the virus enabled the transfer of GBA1 in vast brain regions that resulted spared by the accumulation of a-synuclein toxic aggregates protecting the neurons for the disease.  Thus, progression of the disease was arrested in the treated parkinsonian mice that preserved their locomotor and cognitive skills and increased their life expectancy.

Mutations in the GBA1 gene occur in about 5% of all Parkinson’s patient population and represents the major risk factor for this disease. This gene therapy approach is, therefore, particularly suited for these patients that have a reduced activity of this enzyme. Gene therapy can be designed to activate specific genes enabling to treat sub-group of patients with Parkinson’s disease homogeneous for the pathological molecular mechanism, providing a treatment of precision-medicine more efficacious and with reduced side effects.

Dr. Vania Broccoli, the leading scientist of this work said: “This study reveals that this new class of therapeutic viruses can support a wide distribution of the therapeutic gene throughout the brain protecting neurons from the neurodegenerative process. This virus and its therapeutic gene represent a new class of  “molecular medicine” which discloses new opportunities of treatment for these diseases".

This study has been published in the Molecular Therapy journal and funded by the European Community, the Michael J. Fox Foundation and Regione Lombardia.

The next step will be to validate safety and efficacy of this treatment in a larger number of animals before starting experimentation in patients.

More details can be read in the original work published in the Molecular Therapy scientific journal: AAV-PHP.B-Mediated Global-Scale Expression in the Mouse Nervous System Enables GBA1 Gene Therapy for Wide Protection from Synucleinopathy.

Giuseppe Morabito, Serena G. Giannelli, Gabriele Ordazzo, Simone Bido, Valerio Castoldi, Marzia Indrigo, Tommaso Cabassi, Stefano Cattaneo, Mirko Luoni, Cinzia Cancellieri, Alessandro Sessa, Marco Bacigaluppi, Stefano Taverna, Letizia Leocani, José L. Lanciego, and Vania Broccoli (Molecular Therapy, In press.)

DOI: http://dx.doi.org/10.1016/j.ymthe.2017.08.004

For further information: Vania Broccoli, e-mail: vania.broccoli@in.cnr.it  tel. 02/50316961,

Cnr Press Office: Rita Bugliosi, tel. 06/49932021, -3383, e-mail: rita.bugliosi@cnr.it

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