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Gene therapy shows promise in model of Parkinson’s disease


Scientists at the Ecole Polytechnique Federale de Lausanne (EPFL), Switzerland, have conducted novel experiments that might one day lead to gene therapy treatment options for patients with Parkinson’s disease.

In research published this week in the Proceedings of the National Academy of Sciences, the research team, led by EPFL President Patrick Aebischer, found that viral delivery of a gene associated with Parkinson’s disease protected neurons from degeneration.

Parkinson’s disease is a progressive, degenerative neurological disorder in which dopamine-producing neurons in the part of the brain responsible for coordinating muscle movement die or become so damaged that they are no longer able to function. Dopamine is a neurotransmitter, a "chemical messenger" that transfers information from neuron to neuron, ultimately allowing us to use our muscles in a smooth, coordinated way. Disease symptoms, such as tremor, rigidity, difficulty coordinating movement and difficulty with balance begin to manifest themselves when about 80% of a victim’s dopamine-producing neurons have died.

Scientists estimate that Parkinson’s disease affects 1-3 % of people over the age of 60. In the United States alone, 1.5 million people suffer from Parkinson’s disease, and about 60,000 new patients are diagnosed every year. Although it is commonly thought of as a disease of the elderly, 15% of Parkinson’s victims are under the age of 50.

Scientists are not sure what causes Parkinson’s disease. There is no way to prevent its onset and once diagnosed, it has no cure. Treatment is limited to ameliorating symptoms with a variety of therapies, including dopamine-based drug therapy. Only about 5-10 % of Parkinson’s appears to be inherited, and to date five genes have been implicated in patients with a familial history of the disease. Studies of these inherited forms of Parkinson’s have led to insights on its pathogenesis in sporadic or non-inherited cases.

One form of inherited Parkinson’s is associated with mutations in the alpha-synuclein gene that cause overexpression of the alpha-synuclein protein. Alpha-synuclein, in turn, is a major component of the proteinaceous intracellular deposits known as Lewy bodies that are characteristic of sporadic Parkinson’s. This suggests that the disease might be linked to a toxic overaccumulation of alpha-synuclein.

A more common, recessive form of inherited Parkinson’s disease typically strikes before the age of 40 and is linked to a mutation in the parkin gene. The loss of enzyme activity resulting from this mutation leads to an accumulation of protein substrates, including alpha-synuclein, in the cell. In these juvenile Parkinson’s cases Lewy bodies are not generally present.

Both these forms of the disease involve buildup of alpha-synuclein in the cell, and result in cell degeneration and death. All the evidence pointed to the possibility that parkin might play an important role in protecting neurons from toxic overaccumulations of alpha-synuclein. Aebischer, PhD student Christophe Lo Bianco and their colleagues tested this by injecting rats sub-cranially with lentiviral vectors containing the genes for parkin as well as a mutated form of the alpha-synuclein gene. Harmless forms of viruses such as the lentiviral vector are used by researchers because they can efficiently penetrate cells and deliver the gene of interest without inducing a major immune response.

The viruses successfully delivered the genetic material to about 30% of the rat neurons, causing overexpression of parkin and alpha-synuclein. After six weeks, the researchers found that almost all these affected dopamine neurons in rats that had been injected with alpha-synuclein alone had died. In contrast, numerous affected dopamine neurons in animals injected with both parkin and alpha-synuclein were still going strong. The presence of parkin had protected the neurons from alpha-synuclein toxicity.

In addition, rats that had been injected with parkin showed an increase in Lewy body-type intracellular deposits. The researchers postulated that parkin might work to enhance cell survival by somehow transforming soluble toxic proteins into insoluble aggregates.

The findings constitute a significant step forward in understanding the molecular mechanisms behind the disease, says Lo Bianco. "We demonstrated for the first time the feasibility of the gene therapy approach in a genetic model of Parkinson’s disease."

Results of this research might lead to new treatments that could prevent the onset of Parkinson’s disease in genetically predisposed subjects and arrest the disease’s progression once it has been diagnosed, according to Aebischer. "These observations could translate into the clinic either through a direct gene therapy approach or through the identification of small drugs which enhance the expression of the endogenous parkin."

The next step, Lo Bianco notes, is to scale the system up to a primate model. The technique must be able to deliver genetic material to a sufficient number of cells to allow researchers to observe a beneficial effect. In addition, the therapy would have to be meticulously tested for possible side effects and long-term feasibility.

Mary Parlange | EurekAlert!
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