Six-Month Continuous Intraputamenal Infusion Toxicity Study of Recombinant Methionyl Human Glial Cell Line-Derived Neurotrophic Factor (r-metHuGDNF) in Rhesus Monkeys

Hovland, David N.; Boyd, Robert B.; Butt, Mark T.; Engelhardt, Jeffery A.; Moxness, Michael; Mark, Herbert; Emery, Maurice G.; Ernst, N.; Reed, Randall P.; Zeller, Jillynne R.; Gash, Don M.; Masterman, Donna; Potter, B.; Cosenza, Mary Ellen; Lightfoot, Ruth M.

doi:10.1177/01926230701481899a

Cited by 32 publications

(25 citation statements)

References 43 publications

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“…Anti-GDNF binding antibodies in serum were detected in 8 (57.1%) of the 14 GDNF-treated animals (including 2 satellite study animals) and 1 (16.7%) of the 6 control animals (one sample only; isolated positive samples in control animals were also found by Hovland et al 2007). Five (35.7%) of the GDNF-treated animals were also found to have anti-GDNF neutralizing antibodies in serum, and one (7.1%) in addition had positive findings for anti-GDNF binding and neutralizing antibodies in CSF.…”

Section: Resultsmentioning

confidence: 67%

“…Cerebellar lesions, in particular Purkinje cell atrophy, were previously observed in rhesus monkeys treated with a 4-week brain dose of 2800 µg GDNF using continuous unilateral IPu infusion for 6 months ( C i : 0.67 µg/µL) (Hovland et al 2007). In addition, in that study, an increased inflammatory reaction to the foreign protein was seen at the infusion site and along the catheter track with the same dose.…”

Section: Discussionmentioning

confidence: 94%

“…No cerebellar lesions were detected in any low- or medium-dose animals in the same study, or in any animal treated in one of three other subchronic or chronic toxicity studies [IT: one 3-month study ( N = 17); ICV: one 3-month study with 1-month recovery ( N = 24) and one 6-month study with 3-month recovery ( N = 27)] (Hovland et al 2007; Luz et al 2016). Continuous dosing of GDNF in the culprit IPu study was found to be associated with significant dose-dependent GDNF leakage into the cerebrospinal fluid (CSF) compartment (Hovland et al 2007).…”

Section: Introductionmentioning

confidence: 99%

“…The primary GDNF toxicity of potential human relevance was cerebellar Purkinje cell loss which was observed in a chronic continuous IPu dosing study (Hovland et al 2007). In that study, 72 rhesus monkeys were treated with vehicle or 15, 30 or 100 µg GDNF per day [GDNF concentration in the infusate ( C i ): 0, 0.1, 0.2, or 0.67 µg/µL] at an infusion rate of 6.25 µL/h for 6 months (6/sex/group), followed by a 3-month recovery period (3/sex/group).…”

Section: Introductionmentioning

confidence: 99%

“…Continuous dosing of GDNF in the culprit IPu study was found to be associated with significant dose-dependent GDNF leakage into the cerebrospinal fluid (CSF) compartment (Hovland et al 2007). Based on a detailed review of the study data and research conducted since, it was hypothesized that extended leakage-induced exposure to high GDNF concentrations in CSF ( C CSF ) > 1700 pg/mL led to down-regulation of GDNF receptors on Purkinje cells, and that subsequent acute withdrawal of GDNF then resulted in the observed cerebellar lesions (Luz et al 2016).…”

Section: Introductionmentioning

confidence: 99%

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Intermittent convection-enhanced delivery of GDNF into rhesus monkey putamen: absence of local or cerebellar toxicity

Luz

Allen²,

Bringas

et al. 2018

Arch Toxicol

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Glial cell line-derived neurotrophic factor (GDNF) has demonstrated neurorestorative and neuroprotective effects in rodent and nonhuman primate models of Parkinson’s disease. However, continuous intraputamenal infusion of GDNF (100 µg/day) resulted in multifocal cerebellar Purkinje cell loss in a 6-month toxicity study in rhesus monkeys. It was hypothesized that continuous leakage of GDNF into the cerebrospinal fluid compartment during the infusions led to down-regulation of GDNF receptors on Purkinje cells, and that subsequent acute withdrawal of GDNF then mediated the observed cerebellar lesions. Here we present the results of a 9-month toxicity study in which rhesus monkeys received intermittent intraputamenal infusions via convection-enhanced delivery. Animals were treated with GDNF (87.1 µg; N = 14) or vehicle (N = 6) once every 4 weeks for a total of 40 weeks (11 treatments). Four of the GDNF-treated animals were utilized in a satellite study assessing the impact of concomitant catheter repositioning prior to treatment. In the main study, eight animals (5 GDNF, 3 control) were euthanized at the end of the treatment period, along with the four satellite study animals, while the remaining eight animals (5 GDNF, 3 control) were euthanized at the end of a 12-week recovery period. There were no GDNF-related adverse effects and in particular, no GDNF-related microscopic findings in the brain, spinal cord, dorsal root ganglia, or trigeminal ganglia. Therefore, 87.1 µg/4 weeks is considered the no observed adverse effect level for GDNF in rhesus monkeys receiving intermittent, convection-enhanced delivery of GDNF for 9 months.Electronic supplementary materialThe online version of this article (10.1007/s00204-018-2222-z) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Intermittent convection-enhanced delivery of GDNF into rhesus monkey putamen: absence of local or cerebellar toxicity

Luz

Allen²,

Bringas

et al. 2018

Arch Toxicol

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Embryonic substantia nigra grafts in the mesencephalon send neurites to the host striatum in non‐human primate after overexpression of GDNF

Redmond

Elsworth

Roth

et al. 2009

J of Comparative Neurology

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In spite of partial success in treating Parkinson's disease using ectopically placed grafts of dopamineproducing cells, restoration of the original neuroanatomical circuits, if possible, might work better. Previous evidence of normal anatomic projections from ventral mesencephalic (VM) grafts placed in the substantia nigra (SN) has been limited to neonatal rodents and double grafting or bridging procedures. This study attempted to determine whether injection of a potent growth promoting factor, glial cell line-derived neurotrophic factor (GDNF), into the target regions or placement of fetal striatal co-grafts in the nigrostriatal pathway might elicit neuritic outgrowth to the caudate nucleus. Four adult St. Kitts green monkeys received embryonic VM grafts into the rostral mesencephalon near the host substantia nigra, and injections of AAV2/GDNF or EIAV/GDNF into the caudate. Three adult monkeys were co-grafted with fetal VM tissue near the substantia nigra and fetal striatal grafts (STR) 2.5 mm rostral in the nigrostriatal pathway. Before sacrifice, the striatal target regions were injected with the retrograde tracer fluorogold (FG). FG label was found in tyrosine hydroxylaselabeled neurons in VM grafts in the SN of only those monkeys that received AAV2/GDNF vector injections into the ipsilateral striatum. All monkeys showed FG labeling in the host substantia nigra when FG labeling was injected on the same side. These data show that grafted dopaminergic neurons can extend neurites to a distant target releasing an elevated concentration of GDNF, and suggest that grafted neurons can be placed into appropriate loci for potential tract reconstruction.

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Novel CDNF/MANF family of neurotrophic factors

Lindholm

Saarma

2010

Developmental Neurobiology

174

136

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Current therapeutic interventions for neurodegenerative diseases alleviate only disease symptoms, while treatments that could stop or reverse actual degenerative processes are not available. Parkinson's disease (PD) is a movement disorder with characteristic degeneration of dopaminergic neurons in the midbrain. Few neurotrophic factors (NTFs) that promote survival, maintenance, and differentiation of affected brain neurons are considered as potential therapeutic agents for the treatment of neurodegenerative diseases. Thus, it is important to search and study new NTFs that could also be used in therapy. In this review, we discuss novel evolutionary conserved family of NTFs consisting of two members in the vertebrates, cerebral dopamine neurotrophic factor (CDNF) and mesencephalic astrocyte-derived neurotrophic factor (MANF). Invertebrates, including Drosophila and Caenorhabditis have a single protein homologous to vertebrate CDNF/ MANF. Characteristic feature of these proteins is eight structurally conserved cysteine residues, which determine the protein fold. The crystal structure analysis revealed that CDNF and MANF consist of two domains; an amino-terminal saposin-like domain that may interact with lipids or membranes, and a presumably unfolded carboxy-terminal domain that may protect cells against endoplasmic reticulum stress. CDNF and MANF protect midbrain dopaminergic neurons and restore motor function in 6-hydroxydopamine rat model of PD in vivo. In line, Drosophila MANF is needed for the maintenance of dopaminergic neurites and dopamine levels in the fly, suggesting that the function of CDNF/MANF proteins is evolutionary conserved. Future studies will reveal the receptors and mode of action of these novel factors, which are potential therapeutic proteins for the treatment of PD. ' 2010 Wiley Periodicals, Inc. Develop Neurobiol 70: 360-371, 2010

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Six-Month Continuous Intraputamenal Infusion Toxicity Study of Recombinant Methionyl Human Glial Cell Line-Derived Neurotrophic Factor (r-metHuGDNF) in Rhesus Monkeys

Cited by 32 publications

References 43 publications

Intermittent convection-enhanced delivery of GDNF into rhesus monkey putamen: absence of local or cerebellar toxicity

Intermittent convection-enhanced delivery of GDNF into rhesus monkey putamen: absence of local or cerebellar toxicity

Embryonic substantia nigra grafts in the mesencephalon send neurites to the host striatum in non‐human primate after overexpression of GDNF

Novel CDNF/MANF family of neurotrophic factors

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