Letter from Stockholm: Learning From Our Failures

The hunt for so-called disease-modifying interventions for Parkinson’s disease has not been going well of late. In Stockholm this week at the 18th International Congress of Parkinson’s Disease and Movement Disorders, some of the world’s leading researchers gave their differing analyses of what lessons should be learned from the set backs. Neuroscientist Jeff Kordower gave a refreshingly honest account of a 15-year quest to rescue dopaminergic cells with neurotrophic factors delivered via gene therapy. The story started so promisingly. Following some highly impressive primate experiments with GDNF in 2000, Kordower helped found a biotech company, Ceregene, that went on to mount positive open label human trials in which genes that expressed a related but less potent growth factor called Neurturin were surgically delivered to the brain. Unfortunately, subsequent placebo-controlled trials in 2008 and 2013 were a bust. While Ceregene successfully delivered working genes to the right parts of the brain, patients receiving growth factor faired no better than placebo controls.

As Kordower told the audience, he thinks he may know why. In a landmark 2013 study, Kordower and colleagues examined nigrostriatal histopathology in 28 post mortem Parkinsonian brains, from patients who had lived with the disease for between 1 and 27 years. The results were disturbing. Two proteins normally active at dopaminergic terminals – tyrosine hydroxylase and dopamine transporter – had essentially disappeared in patients who’d had Parkinson’s for 5 years. The lack of such dopamine markers in the striatum suggests the possibility that within 5 years of getting a diagnosis from a neurologist a patient has virtually no functioning dopamine nerve endings left. Ceregene’s efforts arguably failed, said Kordower, because the damage was too extensive to modify.

Kordower noted two main lessons. One, don’t put too much faith in open label studies. Two, remember that all animal models are imperfect. Phenomenal gene therapy successes in young monkeys with MPTP-induced Parkinsonism should not lead you to expect the technique will work equally well in elderly humans with progressive idiopathic Parkinson’s disease.

Disruption Ahead!

At a different session, two influential neuroscientists Stan Fahn and Roger Barker squared off as they gave somewhat different views of another classic disease-modifying saga – neural grafting. In November 1987, Lund neuroscientists grafted fetal dopamine neurons into the brain of a 47-year old PD patient, launching a hopeful new era of neural grafting aimed at reversing the symptoms of PD. But after some promising initial results, two negative (and highly publicized) double blind placebo controlled trials (in 2001 and 2003) brought the field to a virtual standstill. Proponents like Barker have continued to argue that the technique can work provided multiple factors – patient selection (i.e. age, type, stage), graft preparation, graft placement, immunotherapy, duration of patient follow up, appropriate study end points etc – are properly controlled. He showed a striking video of two cases, Patient 7 and Patient 15, for whom the procedure clearly worked. These patients, both grafted in the 1990’s, have had PD for almost 30 years, take no dopaminergic medication, yet move remarkably well. On the UPDRS, Patient 7 maintains a score of 22 and Patient 15, a score of 18. PET scans of the patients’ brains shows clear signs of graft-derived dopamine innervation of the striatum.

Stan Fahn, the lead author of one of the sham surgery trials, had a somewhat different take. While Fahn conceded neural grafting can work in some cases, the controlled trials were essential, he argued, to address the issue of placebo effects – known to be powerful in surgical interventions. But perhaps the most damaging finding to come out of these two studies, according to Fahn, concerned the discovery of dyskinesias caused by the grafts. In some cases, the graft-induced dyskinesias or GIDs were large and persistent. Fahn showed a somewhat shocking video of a woman graft recipient displaying severe facial dyskinesias; dyskinesias that continued years after she had stopped L-dopa medication.

Even though Barker and Fahn may disagree about the potential of neural grafting and the merits of sham surgery trials, both scientists concurred that the data taken as a whole indicated that younger patients – in their 40s – did far better than older patients.

The saga is not over. The next chapter of the neural grafting story starts later this month as the first patients are enrolled in the TRANSEURO program.