I understand that further animal toxicity studies are in progress. However, over 100 patients have received intracerebral GDNF infusion by one route or another with no clinical toxicity and I can't believe that GDNF treatment won't be available again, at least in some form, in the medium term. To date, the immunogenicity of the recombinant GDNF has not proven to be of clinical significance, but could in any case be circumvented by implantation of autologous or encapsulated eukaryotic cells, genetically modified to secrete GDNF. Stimulating metabolic pathways that induce the synthesis of GDNF sounds attractive but poses problems of targeting, delivery, and specificity. I suggest that this is a less promising option, but would be happy to be proven wrong.
The report by Love and colleagues in Nature Medicine provides intriguing preliminary evidence for a biological effect of GDNF in humans with Parkinson disease. The greater area of staining for tyrosine hydroxylase in the striatum on the side previously most affected by Parkinson disease suggests that GDNF stimulated neuronal sprouting and that this accounted for the increase in fluorodopa uptake seen on positron emission tomography. These observations are exciting but leave many unanswered questions. Is the change in striatal tyrosine hydroxylase and fluorodopa PET sufficient to account for the 38 percent reduction (i.e., improvement) in motor scores? Even more impressive changes in both of these parameters are seen following fetal nigral transplantation, but clinical benefit has been disappointing in double-blind placebo-controlled trials. Love and colleagues present additional results of GFAP and GAP43 immunohistochemistry; however, similar control data from normal and untreated parkinsonian brains were not provided for comparison. Finally, although the results are potentially important in demonstrating a biological effect of this treatment, they also raise questions about the early and bilaterally symmetrical clinical benefit reported following open-label unilateral infusion by Slevin et al., since Love’s patient showed very clear progression on the non-infused side.
The double-blind placebo-controlled trial failed to demonstrate significant efficacy of bilateral intraputamenal GDNF infusion. Importantly, this trial utilized a different catheter and somewhat different doses than were used in the patient reported by the Bristol group. It is not known whether these differences could account for the contrasting results of the open-label and double-blind studies. In addition, a similar change in fluorodopa PET to that originally reported by Gill and colleagues) was obtained in the double-blind trial despite the lack of benefit. During this trial and its open-label extension, 10 percent of patients developed blocking antibodies to GDNF, and subsequently, studies in primates demonstrated evidence for an unusual cerebellar toxicity. The clinical implications of these two findings for humans with Parkinson disease are unknown. In the face of a negative double-blind clinical trial and the development of these safety issues, Amgen chose to discontinue further use of this treatment in Parkinson disease. Subsequently, two patients from New York took the company to court demanding that continued treatment with GDNF be made available to them. The court found in favor of Amgen and the lawsuit was dismissed. Unfortunately, the current formulation of recombinant GDNF as manufactured by Amgen will probably not be used again in patients with Parkinson disease unless further basic studies can resolve these potentially important safety issues. It is hoped that other trophic factors or other methods of applying GDNF (e.g., gene therapy or cell-based therapies) will fulfill the promise of this approach in Parkinson disease. Finally, it should be emphasized that many of the problems we face in managing late-stage Parkinson disease do not stem from striatal dopamine deficiency, and therefore would not be expected to respond to even the most effective rejuvenation or replacement of the nigrostriatal dopamine system.
References:
Gill SS, Patel NK, Hotton GR, O'Sullivan K, McCarter R, Bunnage M, Brooks DJ, Svendsen CN, Heywood P.
Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease.
Nat Med. 2003 May;9(5):589-95.
PubMed.
Slevin JT, Gerhardt GA, Smith CD, Gash DM, Kryscio R, Young B.
Improvement of bilateral motor functions in patients with Parkinson disease through the unilateral intraputaminal infusion of glial cell line-derived neurotrophic factor.
J Neurosurg. 2005 Feb;102(2):216-22.
PubMed.
Comments
University of Bristol
I understand that further animal toxicity studies are in progress. However, over 100 patients have received intracerebral GDNF infusion by one route or another with no clinical toxicity and I can't believe that GDNF treatment won't be available again, at least in some form, in the medium term. To date, the immunogenicity of the recombinant GDNF has not proven to be of clinical significance, but could in any case be circumvented by implantation of autologous or encapsulated eukaryotic cells, genetically modified to secrete GDNF. Stimulating metabolic pathways that induce the synthesis of GDNF sounds attractive but poses problems of targeting, delivery, and specificity. I suggest that this is a less promising option, but would be happy to be proven wrong.
View all comments by Seth LoveToronto Western Hospital
The report by Love and colleagues in Nature Medicine provides intriguing preliminary evidence for a biological effect of GDNF in humans with Parkinson disease. The greater area of staining for tyrosine hydroxylase in the striatum on the side previously most affected by Parkinson disease suggests that GDNF stimulated neuronal sprouting and that this accounted for the increase in fluorodopa uptake seen on positron emission tomography. These observations are exciting but leave many unanswered questions. Is the change in striatal tyrosine hydroxylase and fluorodopa PET sufficient to account for the 38 percent reduction (i.e., improvement) in motor scores? Even more impressive changes in both of these parameters are seen following fetal nigral transplantation, but clinical benefit has been disappointing in double-blind placebo-controlled trials. Love and colleagues present additional results of GFAP and GAP43 immunohistochemistry; however, similar control data from normal and untreated parkinsonian brains were not provided for comparison. Finally, although the results are potentially important in demonstrating a biological effect of this treatment, they also raise questions about the early and bilaterally symmetrical clinical benefit reported following open-label unilateral infusion by Slevin et al., since Love’s patient showed very clear progression on the non-infused side.
The double-blind placebo-controlled trial failed to demonstrate significant efficacy of bilateral intraputamenal GDNF infusion. Importantly, this trial utilized a different catheter and somewhat different doses than were used in the patient reported by the Bristol group. It is not known whether these differences could account for the contrasting results of the open-label and double-blind studies. In addition, a similar change in fluorodopa PET to that originally reported by Gill and colleagues) was obtained in the double-blind trial despite the lack of benefit. During this trial and its open-label extension, 10 percent of patients developed blocking antibodies to GDNF, and subsequently, studies in primates demonstrated evidence for an unusual cerebellar toxicity. The clinical implications of these two findings for humans with Parkinson disease are unknown. In the face of a negative double-blind clinical trial and the development of these safety issues, Amgen chose to discontinue further use of this treatment in Parkinson disease. Subsequently, two patients from New York took the company to court demanding that continued treatment with GDNF be made available to them. The court found in favor of Amgen and the lawsuit was dismissed. Unfortunately, the current formulation of recombinant GDNF as manufactured by Amgen will probably not be used again in patients with Parkinson disease unless further basic studies can resolve these potentially important safety issues. It is hoped that other trophic factors or other methods of applying GDNF (e.g., gene therapy or cell-based therapies) will fulfill the promise of this approach in Parkinson disease. Finally, it should be emphasized that many of the problems we face in managing late-stage Parkinson disease do not stem from striatal dopamine deficiency, and therefore would not be expected to respond to even the most effective rejuvenation or replacement of the nigrostriatal dopamine system.
References:
Gill SS, Patel NK, Hotton GR, O'Sullivan K, McCarter R, Bunnage M, Brooks DJ, Svendsen CN, Heywood P. Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease. Nat Med. 2003 May;9(5):589-95. PubMed.
Slevin JT, Gerhardt GA, Smith CD, Gash DM, Kryscio R, Young B. Improvement of bilateral motor functions in patients with Parkinson disease through the unilateral intraputaminal infusion of glial cell line-derived neurotrophic factor. J Neurosurg. 2005 Feb;102(2):216-22. PubMed.
View all comments by Anthony Lang