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GDNF has been hailed as a potential breakthrough for Parkinson’s ever since it was discovered in 1993. In the lab, it was shown to bring dying brain cells back to life and it has proved to be particularly effective on dopamine neurons, the ones lost in Parkinson’s. However, the intervening years have seen the drug mired in controversy.

What is GDNF?

Our brains contain two main types of cells: neurons and glial cells. Although less well-known, glial cells actually make up 90% of brain cells. Their name comes from “glia” - Latin for “glue.” Initially thought to play only a supporting role, glial cells are now known to be critical in synapse formation. They also nourish neurons with chemicals called “neurotrophic factors” (from the Greek for “nerve-feeding”).

Glial Cell-Derived Neurotrophic Factor (GDNF) is one of these.

• In 1952 Rita Levi–Montalcini isolates a substance from tumors in mice that causes vigorous nervous system growth in chicken embryos. Her findings lead to the discovery of nerve growth factors: proteins native to the human body, including GDNF. In 1986, she and Stanley Cohen win the Nobel Prize in Physiology or Medicine. Their work provides deeper understanding of deformities, senile dementia, delayed wound healing, and tumor diseases. At the time, she was one of a dozen or so women to receive the Nobel Prize in science.
• In 1993, in a breakthrough study, GDNF is found in the lab to bring dying dopamine neurons back to life (Lin et al.) Researchers note it could be useful in treating Parkinson’s, for which there are no treatments to prevent continued degeneration of neurons.
• A 1996 study (Gash, et al.) GDNF proves effective in improving the symptoms of Parkinson’s-like symptoms in monkeys.
• Late 90s to mid-2000s: Other animal studies confirm GDNF’s utility in animal models of Parkinson’s and also in spinal cord injuries.
• A 1999 study (Kordower, et al.) shows that delivering GDNF via intraventricular injection does not deliver it to the correct part of the brain. Post-mortem brain scans of one patient who died (unrelated to the trial) show no reduction in Parkinson’s symptoms and no evidence of structural repair in the brain. The patient did however experience unwanted side effects, including nausea, tingling, and hallucinations.
• In 2001, Steve Gill is the first to administer GDNF directly into the putamen in a Phase I study of people with Parkinson’s. By implanting a catheter into the brain, he solves a problem from earlier studies, where GDNF did not access the target area (because it cannot cross the blood-brain barrier, it must be delivered directly into the brain). After one year, the five patients show a 39% improvement in their off-medication motor scores. They improve more than 60% in their UPDRS scores - a unified rating system that assesses the progression of Parkinson’s. One patient even returns to work after being on disability. However, the Phase I trial does not have a placebo arm, casting doubt over the results.
• 2004 - Pharmaceutical company Amgen halts a Phase II GDNF trial after six months. Amgen cites safety concerns when some patients develop antibodies to the treatment. It points to another study showing that some monkeys on large doses of GDNF develop lesions in their brains. The trial’s premature end sparks international controversy, with some, including author Nick Nelson (“Monkey in the Middle: How One Drug Company Kept a Parkinson’s Disease Breakthrough Out of Reach”) claiming that the decision was financial.
• 2019. Phase 2 trial in Bristol (“Randomized Parkinson's Trial of GDNF Administered via Intermittent Intraputamenal Convection-Enhanced Delivery”, Whone et al, Brain, March 2019) fails to show significant improvement in motor scores at 40 weeks, but finds a 30% improvement in the 40-week open-label extension study that followed. The GDNF group showed highly significantly increased 18F-DOPA uptake throughout the entire putamen that reached 100% improvement in the posterior portion.

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More about the GDNF trial:

Trial scientific papers

The scientific findings from the GDNF trial have been published in two peer-reviewed scientific journals.

The main part of the trial is published in “Brain":

The extension study (the second 9 months of the trial during which everyone received the drug GDNF) is published in the Journal of Parkinson’s Disease: