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ProSavin, a gene therapy, for Parkinson's disease yields promising results in first patients

A new gene therapy for Parkinson's disease has achieved promising results in its first human tests, involving 15 patients.
Nicholas Mazarakis, Gene Therapy at the Imperial College London, devised the approach while working at biopharmaceutical company Oxford BioMedica in 1997. Sixteen years later, the results of the first tests in humans have been published in The Lancet.

The treatment, called ProSavin, uses a modified virus to deliver three genes into the striatum, a part of the brain that controls movement. The genes are intended to boost the production of dopamine, a chemical that becomes deficient in patients with Parkinson’s.

Current treatments can boost dopamine production temporarily, but the cells that produce dopamine continue to degenerate until the treatments are no longer effective.

The new therapy aims to provide a long-term solution by stimulating dopamine to be produced in a different set of cells.

Other gene therapies have been tried in Parkinson’s disease, but all employ a different approach. Mazarakis’s strategy is to deliver three genes that code for enzymes that produce dopamine. They are smuggled into the brain by a lentivirus, closely related to HIV, which incorporates its genetic material into the genome of the cells it infects, ensuring a long-lasting effect.

After first testing the treatment in rats, Oxford Biomedica worked with Stéphane Palfi’s group at the University of Paris to carry out a study in macaques.
Researchers showed that the treatment corrected the movement deficits of the monkeys for up to three and a half years, without any visible adverse effects. Notably, it didn’t result in abnormal involuntary movements caused by treatments in use today.

Those results paved the way for the first tests in humans. Before beginning a double-blind, placebo-controlled trial straight away the researchers decided to test different doses on a small group of patients.

The trial participants, three in the UK and 12 in France, all in the advanced stages of the disease, underwent a single operation to inject the virus into the brain.

The treatment has been safe, with no serious adverse effects. The patients’ scores on movement tests have improved on average by 30%, and they also report having a better quality of life. The first patients to have the surgery have now been followed up for four years, and the effect has been sustained. PET scans confirm that dopamine is being produced in the brain where it wasn’t before.

In such a small study, it’s difficult to compare the effects of different doses, but there are indications that the highest dose had the strongest effect. Patients on the highest dose all had to reduce their use of standard dopamine replacement therapy, as in combination with the gene therapy it caused side effects related to excessive dopamine.
The absence of a placebo group for comparison means the results have to be interpreted with caution, but the researchers are certainly optimistic.

Parkinson’s disease, which affects around five million people worldwide, is a neurological disease that affects patients’ movement. The main symptoms are involuntary shaking of particular parts of the body, known as tremor; muscle stiffness, known as rigidity; and physical movements becoming very slow, known as bradykinesia. In the advanced stages, patients are often unable to do everyday tasks like washing and dressing without help from a carer.

Parkinson's is caused by a loss of nerve cells in the part of the brain called the substantia nigra. The loss of nerve cells is a slow process, causing a gradual reduction in levels of dopamine, a brain chemical produced by these cells. Symptoms only become severe when 80% of the nerve cells in the substantia nigra have been lost.

It is not known why the loss of nerve cells associated with Parkinson's disease occurs. Genetic factors and exposure to toxins are considered to be possible causes.

Current therapies are mainly based on Levodopa, a precursor that gets converted into dopamine in the brain. They are usually very effective at first, but over time they become less effective as there are fewer nerve cells left to produce dopamine. They can also cause severe side effects, such as uncontrollable jerky movements, known as dyskinesia. ( Xagena )

Source: Imperial College London, 2014