Development of a Maturing T-Cell-Mediated Immune Response in Patients with Idiopathic Parkinson’s Disease Receiving r-metHuGDNF Via Continuous Intraputaminal Infusion

Tatarewicz, Suzanna; Wei, Xin; Gupta, Shalini; Masterman, Donna; Swanson, Steven J.; Moxness, Michael

doi:10.1007/s10875-007-9117-8

Cited by 64 publications

(45 citation statements)

References 36 publications

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“…Initial clinical trials involved administering GDNF protein, with mixed results ( Refs 37,38,39,40,41,42). The appearance of GDNF antibodies in some patients (Refs 41, 42) highlighted a need to approach NTF therapy differently.…”

Section: Discussionmentioning

confidence: 99%

Viral vector delivery of neurotrophic factors for Parkinson's disease therapy

O’Keeffe

Sullivan

2015

Expert Rev. Mol. Med.

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Parkinson's disease (PD) is a neurodegenerative disorder characterised by the progressive loss of midbrain dopaminergic neurons, which causes motor impairments. Current treatments involve dopamine replacement to address the disease symptoms rather than its cause. Factors that promote the survival of dopaminergic neurons have been proposed as novel therapies for PD. Several dopaminergic neurotrophic factors (NTFs) have been examined for their ability to protect and/or restore degenerating dopaminergic neurons, both in animal models and in clinical trials. These include glial cell line-derived neurotrophic factor, neurturin, cerebral dopamine neurotrophic factor and growth/differentiation factor 5. Delivery of these NTFs via injection or infusion to the brain raises several practical problems. A new delivery approach for NTFs involves the use of recombinant viral vectors to enable long-term expression of these factors in brain cells. Vectors used include those based on adenoviruses, adeno-associated viruses and lentiviruses. Here we review progress to date on the potential of each of these four NTFs as novel therapeutic strategies for PD, as well as the challenges that have arisen, from pre-clinical analysis to clinical trials. We conclude by discussing recently-developed approaches to optimise the delivery of NTF-carrying viral vectors to the brain.

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Section: Discussionmentioning

confidence: 99%

Viral vector delivery of neurotrophic factors for Parkinson's disease therapy

O’Keeffe

Sullivan

2015

Expert Rev. Mol. Med.

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“…GDNF-binding antibodies appeared in the serum of approximately half the subjects, and GDNFneutralizing antibodies developed in a small subset of these same subjects. 85 Finally, the concurrent 6-month toxicity studies found a patchy loss of Purkinje cells in some monkeys on high-dose GDNF (100 g/day). Although there was no toxicity attributable to GDNF in the clinical trials, these findings, added to the lack of efficacy in the randomized clinical trial, led Amgen to discontinue the clinical studies.…”

Section: Intraputaminal Administration Of Gdnfmentioning

confidence: 98%

Treatment of Parkinson’s Disease with Trophic Factors

2008

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Summary: Trophic factors are proteins that support and protect subpopulations of cells. A number have been reported to act on dopaminergic neurons in vitro and in vivo, making them potential therapeutic candidates for Parkinson's disease. All of these candidate factors protect dopaminergic neurons if given prior to, or with, selective neurotoxins. Fewer trophic factors, primarily glial-derived neurotrophic factor (GDNF) and its relative, neurturin (NRTN; also known as NTN), have been shown to restore function in damaged dopamine neurons after the acute effects of neurotoxins have subsided. A major barrier to clinical translation has been delivery. GDNF delivered by intracerebroventricular injection in patients was ineffective, probably because GDNF did not reach the target, the putamen, and intraputaminal infusion was ineffective, probably because of limited distribution within the putamen. A randomized clinical trial with gene therapy for NRTN is underway, in an attempt to overcome these problems with targeting and distribution. Other strategies are available to induce trophic effects in the CNS, but have not yet been the focus of human research. To date, clinical trials have focused on restoration of function (i.e., improvement of parkinsonism). Protection (i.e., slowing or halting disease progression and functional decline) might be a more robust effect of trophic agents. Laboratory research points to their effectiveness in protecting neurons and even restoring dopaminergic function after a monophasic neurotoxic insult. Utility for such compounds in patients with Parkinson's disease and ongoing loss of dopaminergic neurons remains to be proven.

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“…After six months of bilateral intraputaminal infusion of recombinant GDNF, there were no significant differences between the motor scores of the unified Parkinson's disease rating scale (UPDRS) in patients that had received GDNF and in those that had received a placebo. Furthermore, safety concerns were raised, since approximately 10% of the GDNF-treated patients developed antibodies against the peptide, which could potentially counteract the therapeutic benefits [131]. A similar proportion of patients who had participated in the two open-label trials also developed antibodies to GDNF [129,130].…”

Section: Gdnf In Clinical Trialsmentioning

confidence: 99%