Dose-Escalation Trial of Continuously Infused Recombinant-Methionyl Human Glial Cell Line-Derived Neurotrophic Factor for the Treatment of PSP

This study will examine the safety and effectiveness of an experimental drug called GDNF delivered through an investigational device to treat progressive supranuclear palsy (PSP). The drug will be administered directly into the brain through catheters attached to an infusion pump implanted in the abdomen. The study will evaluate 1) if the drug is safe and well tolerated when given by this method; 2) the performance of the catheters and pump system, and 3) the effects of GDNF on PSP symptoms.

PSP is a rare neurological disease that causes eye movement dysfunction, muscle rigidity, slowness of movement, swallowing, speech, emotional, cognitive and personality problems. Patients 35 to 75 years old with PSP may be eligible for this study. Candidates will be screened at the National Institutes of Health outpatient clinic in Bethesda, MD, with a medical history, physical examination, neurological and neuropsychiatric evaluations, blood tests, electrocardiogram, CT scan of the brain, and baseline studies including a special eye examination, evaluation of symptoms, lumbar puncture (spinal tap) and psychiatric interview.

Patients enrolled in the study will undergo surgery to place two catheters into the brain and two infusion pumps under the skin in the upper abdomen. The surgery will be performed at Vanderbilt University Medical Center in Nashville, TN. It will be done under general anesthesia and will require a 3 day hospitalization. Within 24 hours after the surgery, a CT scan of the brain will be done to ensure the catheters are properly placed. Patients return to NIH two weeks after surgery for post-surgery examination and treatment initiation.

All patients will receive continuous infusions of GNDF through one catheter and placebo (an inactive salt solution) through the other for 6 months. Half of the patients will receive placebo in the right side of the brain and GNDF in the left, and half will receive GNDF in the right side of the brain and placebo in the left. All patients will also undergo the following procedures:

Brief physical examination, and evaluation of symptoms and adverse side effects - every 2 weeks

Blood and urine tests - every 2 weeks for the first 2 months and then every 8 weeks until the end of the study

CT scan to check catheter placement - weeks 9 and 27

Thorough evaluation of symptoms - before beginning treatment and weeks 1, 5, 9, 17 and 27

Neuropsychiatric evaluation - week 27

Special eye examination - weeks 1 and 27

Lumbar puncture - week 27

Additional blood tests to measure drug concentration and antibodies - 6 times during the study

In addition, some patients may be asked to have positron emission tomography (PET) scans or a single photon emission tomography (SPECT) scan, or both.

The potential benefit of GDNF is unknown. In studies with rats and monkeys, GNDF increased the number and size of brain cells containing the chemical messenger dopamine and some movement and balance problems were lessened. Earlier studies of GDNF infused into the ventricles of patients with Parkinson's disease showed no benefit and no serious harm.