Common drug shuts down gene therapy in rats, addressing safety concerns for humans
A common antibiotic can function as an "off switch" for a gene therapy being developed for Parkinson's disease, according to University of Florida researchers writing online in advance of September's Molecular Therapy.
The discovery in rats answers an important question - how can new, therapeutic genes that have been irrevocably delivered to the human brain to treat Parkinson's be controlled if the genes unexpectedly start causing problems?
Meanwhile, in a review of Parkinson treatments, the researchers say that prior experimental attempts using growth factors - naturally occurring substances that cause cells to grow and divide - to rescue dying brain cells may have failed because they occurred too late in the course of the disease.
Together, the findings suggest that gene therapy to enable the brain to retain its ability to produce dopamine, a neurotransmitter that falls in critically short supply in Parkinson's patients, could be safely attempted during earlier stages of the disease with an added likelihood of success.
Parkinson's disease affects more than 1 million Americans, causing patients to gradually develop movement problems, including tremors, stiffness and slowness. It is caused by degeneration and death of nerve connections that produce dopamine, a substance necessary for communication between cells that coordinate movement.
"We have worked every day for 10 years to design a construct to the gene delivery vector that enhances the safety profile of gene transfer for Parkinson's disease," said Ronald Mandel, a professor of neuroscience at UF's McKnight Brain Institute and the Powell Gene Therapy Center. "With that added measure of safety, we believe we can intervene with gene transfer in patients at earlier stages of the disease. We strongly believe that trials to save dopamine-producing connections in patients with Parkinson's disease have failed because the therapy went into patients who were in the late stages of the disease and who had too few remaining dopamine-producing connections."
Often patients are given prescriptions for levodopa, or L-dopa, which is converted into dopamine by enzymes in the brain. But the treatment loses its effectiveness over time and does nothing to slow the disease's progression.
Meanwhile, trials in the United States to treat Parkinson's involving direct infusion of growth factors or the transplantation of genes that produce growth factors have had limited success, with some side effects.
Mandel's research group has concentrated on using an adeno-associated virus to engineer brain cells in animal models with genes that can protect dopamine-producing cells, which then do the vital work of producing GDNF, short for glial cell line-derived neurotrophic factor. The naturally occurring protein is important for the survival of dopamine-producing neurons during brain development, and a survival factor when given to adults.
In this case, scientists engineered the virus with two genes that must act in concert to produce the protein. But this precise interaction can be inhibited with dietary doxycycline, an antibiotic that is often prescribed in low doses to treat bacterial growth related to acne.