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Gene Therapy Rescues Monkeys from Parkinson's Symptoms

For release: Wednesday, July 14, 2010

Microscopic images show that there are more dopamine-producing nerve fibers in the brains of Parkinsonian monkeys after treatment with AAV-GDNF.

In work funded by the National Institute of Neurological Disorders and Stroke (NINDS), researchers have found they can rescue monkeys from a Parkinson’s-like condition by using gene therapy to deliver a growth factor into the brain.  The approach is among the first that is beneficial to animals after they have developed signs of disease.

Parkinson’s disease attacks a part of the brain that controls movement, called the substantia nigra.  The disease leads to progressive loss of motor function including involuntary shaking, slowed movement, stiffened muscles, and impaired balance.  Drugs and other treatments are available to control these symptoms, but there are no treatments to curb the destruction of neurons in the substantia nigra.

In prior studies of animal models of Parkinson’s, researchers saw glimmers of success by injecting proteins that simulate neuronal growth into the animals’ brains.  A protein called glial-derived neurotrophic factor (GDNF) showed the most promise.  In clinical trials, however, GDNF injections have failed to slow the course of the disease, and in some cases, the injections have caused side effects such as severe weight loss.

One reason for the discrepancy is that in the animal studies, the protein usually was given before the disease started.  “This is not what we’re trying to achieve in patients.  We want to reverse the process in patients with advanced disease,” said Krystof Bankiewicz, M.D., Ph.D., a professor in the Neurosurgery and Neurology departments at the University of California, San Francisco (UCSF).

There were also problems with ensuring that the GDNF protein reached the right places in the brain and that it would persist at stable levels after a limited number of injections.  As a solution, Dr. Bankiewicz’s team at UCSF has been exploring a gene therapy approach – in which the gene for GDNF is packaged into a small virus (adeno-associated virus, or AAV) that is injected into the brain.  If all goes according to plan, neurons near the injection site take up the virus and stably express the GDNF gene.

The latest study from Dr. Bankiewicz’s lab appears in the July 14th issue of the Journal of Neuroscience*

“There have been many challenges in developing a treatment that can restore function in patients with Parkinson’s disease.  Investigators have learned a lot from past experience, and we are hopeful that this approach – in which a potent growth factor is delivered to the brain in a precisely controlled way – will prove beneficial in clinical trials,” said Beth-Anne Sieber, Ph.D., a program director at NINDS.

In the new study, monkeys were given a toxin (called MPTP) that destroys the same cells that are lost in Parkinson’s disease.  Several months after the monkeys developed Parkinson’s-like symptoms, they received AAV-GDNF gene therapy by injections into the putamen, a brain region that connects to the subsantia nigra.  For more precise delivery, the researchers used a high-pressure injection system, unlike previous studies where GDNF was injected under low pressure and allowed to spread by passive flow.  As a control, other monkeys received sham saline injections.

Monkeys given the saline injections remained symptomatic, but monkeys that received the GDNF-virus injections got better.  They showed an average 50 percent improvement on a symptom rating scale after 9 months, with smaller continued improvements out to 2 years.

The treated animals also maintained a higher density of neurons that produce the brain chemical dopamine – the same neurons that disappear in Parkinson’s disease.  Live imaging of the brain by positron emission tomography (PET) scanning, which has been used to gauge treatment effects in clinical studies of Parkinson’s, showed that those neurons remained active.  When Dr. Bankiewicz and his team looked for GDNF in the animals’ brains, they found that it had been taken up by neurons in the putamen and transported along nerve fibers to the substantia nigra, where it was needed.

Most of the treated animals showed no signs of toxicity.  One animal had significant weight loss, and the researchers found that its injection catheter was slightly out of place.  This may have allowed AAV-GDNF to enter the cerebrospinal fluid that fills the brain and spinal cord, and reach other parts of the brain that control appetite and metabolism.  

Similar problems with AAV-GDNF delivery may have caused the weight loss seen in past clinical trials.  In the trials, the injections were performed as standard neurosurgery on an operating table, so there was no way to ensure that virus was delivered correctly and that it did not leak into the cerebrospinal fluid or blood.  Dr. Bankiewicz and his team have found a workaround to this problem.   In the June 2010 issue of Molecular Therapy**, they reported they could track the flow of the virus in the monkey brain by pre-loading it with a tracer visible by magnetic resonance imaging (MRI).

A clinical trial to test the safety of AAV-GDNF is planned.  In a workup for the trial, the NIH Rapid Access to Interventional Development (NIH RAID) program is supporting additional toxicity studies, as well as the production of clinical grade virus.

To date, only a handful of gene therapy approaches have entered clinical trials for Parkinson’s disease.  In ongoing trials based on research in Dr. Bankiewicz’s lab, one strategy is to rescue ailing neurons by giving them extra copies of an enzyme called AADC, which stimulates the production of dopamine.  So far, the trials have shown that injection of AAV-AADC into the putamen appears safe, but it is too early to tell whether the treatment is effective.  In another recent trial, patients received intra-putamenal injections of AAV carrying the Neurturin gene, which encodes a protein related to GDNF.  The treatment failed, but another trial of AAV-Neurturin is underway using a modified protocol.

-By Daniel Stimson, Ph.D.

*Kells AP et al.  “Regeneration of the MPTP-Lesioned Dopaminergic System after Convection-Enhanced Delivery of AAV2-GDNF.”  Journal of Neuroscience, Vol. 30 (no. 28), July 14, 2010.

**Su X et al.  “Real-time MR Imaging With Gadoteridol Predicts Distribution of Transgenes After Convection-enhanced Delivery of AAV2 Vectors.”  Molecular Therapy, published online June 15, 2010.

 Microscopic images show that there are more dopamine-producing nerve fibers in the brains of Parkinsonian monkeys after treatment with AAV-GDNF.
Dopamine-producing nerve fibers (black, wavy lines) in the putamen of Parkinsonian monkeys 14 months after AAV-GDNF (top) or without treatment (bottom). Image courtesy of Dr. Krystof Bankiewicz, UCSF.

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Last Modified February 9, 2011