Targeted Delivery of GDNF to Areas of the Brain Improves Parkinson's Symptoms

The overt Parkinson's disease are in part caused by the loss of a small but critical population of dopamine-generating neurons in the brain. As is the case for many neurodegenerative diseases, however, the creation of protein aggregates and resultant dysfunctional biochemistry is also important in Parkinson's. That causes a range of further issues beyond loss of motor control. The focus here is nonetheless on an attempt to regenerate lost dopamine-generating neurons, accomplished by delivering the protein GDNF into the brain over a sustained period of time, and in a very precise, narrowly targeted way. Trial results indicate an improvement in the condition of patients, providing additional support for use of the strategy of restoring lost neurons, even in the absence of any attempt to address the protein aggregation of Parkinson's disease. Though that said, I have to think that meaningful, long-term reversal of the condition will require the protein aggregates to be cleared.

A pioneering clinical trials program that delivered an experimental treatment directly to the brain offers hope that it may be possible to restore the cells damaged in Parkinson's disease. Six patients took part in the initial pilot study to assess the safety of the treatment approach. A further 35 individuals then participated in the nine-month double blind trial, in which half were randomly assigned to receive monthly infusions of Glial Cell Line Derived Neurotrophic Factor (GDNF) and the other half placebo infusions. After the initial nine months on GDNF or placebo, the open-label extension study took place, which explored the effects and safety of continued exposure to GDNF for another 40 weeks in the patients previously receiving GDNF (80 weeks in total) and the effects of 40 weeks of open label GDNF in those subjects who had previously received placebo for the first 40 weeks.

A specially designed delivery system was implanted using robot-assisted neurosurgery. This delivery system allowed high flow rate infusions to be administered every four weeks. Four tubes were carefully placed into each patient's brain, which allowed GDNF to be infused directly to the affected areas with pinpoint accuracy via a skull-mounted transcutaneous port behind the ear. After implantation and over the following several years the trial team administered more than 1000 brain infusions, once every four weeks over 18 months to study participants.

After nine months, there was no change in the PET scans of those who received placebo, whereas the group who received GDNF showed an improvement of 100% in a key area of the brain affected in the condition, offering hope that the treatment was starting to reawaken and restore damaged brain cells. By 18 months, when all participants had received GDNF, both groups showed moderate to large improvements in symptoms compared to before they started the study and that GDNF was safe when administered over this length of time. "This trial has shown that we can safely and repeatedly infuse drugs directly into patients' brains over months or years. This is a significant breakthrough in our ability to treat neurological conditions."



A bit of a positive spin on the trial results. New Scientist's report is a bit more balanced (though the headline is on the pessimistic side):

Also, sticking tubes in people's brains seems a bit, umm, sledgehammer-ish (but if that's all that's available and people are dying, sure why not). Exosomal delivery or focused ultrasound seem like better ways to get things into the brain.

PD patients have been reporting symptom reversal on nilotinib (people in trials or have obtained the drug off-label or from overseas).

Posted by: CD at March 5th, 2019 11:30 AM

Forgot to mention that nilotinib is also being used off-label by patients with progressive supranuclear palsy, a tau pathology. I've also seen a report by a patient from Korea using nilotinib in a trial for spinocerebellar ataxia type 1 (SCA1, accumulation of ataxin-1 aggregates).

Posted by: CD at March 6th, 2019 11:32 AM
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