Clearance and Toxicity of Recombinant Methionyl Human Glial Cell Line-Derived Neurotrophic Factor (r-metHu GDNF) Following Acute Convection-Enhanced Delivery into the Striatum
Identifieur interne : 000E40 ( Main/Merge ); précédent : 000E39; suivant : 000E41Clearance and Toxicity of Recombinant Methionyl Human Glial Cell Line-Derived Neurotrophic Factor (r-metHu GDNF) Following Acute Convection-Enhanced Delivery into the Striatum
Auteurs : Hannah Taylor [Royaume-Uni] ; Neil Barua [Royaume-Uni] ; Alison Bienemann [Royaume-Uni] ; Marcella Wyatt [Royaume-Uni] ; Emma Castrique [Royaume-Uni] ; Rebecca Foster [Royaume-Uni] ; Matthias Luz [Canada] ; Christian Fibiger [Canada] ; Erich Mohr [Canada] ; Steven Gill [Royaume-Uni]Source :
- PLoS ONE [ 1932-6203 ] ; 2013.
Abstract
Despite promising early results, clinical trials involving the continuous delivery of recombinant methionyl human glial cell line-derived neurotrophic factor (r-metHuGDNF) into the putamen for the treatment of Parkinson's disease have shown evidence of poor distribution and toxicity due to point-source accumulation. Convection-enhanced delivery (CED) has the potential to facilitate more widespread and clinically effective drug distribution.
We investigated acute CED of r-metHuGDNF into the striatum of normal rats in order to assess tissue clearance, toxicity (neuron loss, gliosis, microglial activation, and decreases in synaptophysin), synaptogenesis and neurite-outgrowth. We investigated a range of clinically relevant infused concentrations (0.1, 0.2, 0.6 and 1.0 µg/µL) and time points (2 and 4 weeks) in order to rationalise a dosing regimen suitable for clinical translation.
Two weeks after single dose CED, r-metHuGDNF was below the limit of detection by ELISA but detectable by immunohistochemistry when infused at low concentrations (0.1 and 0.2 µg/µL). At these concentrations, there was no associated neuronal loss (neuronal nuclei, NeuN, immunohistochemistry) or synaptic toxicity (synaptophysin ELISA). CED at an infused concentration of 0.2 µg/µL was associated with a significant increase in synaptogenesis (p<0.01). In contrast, high concentrations of r-metHuGDNF (above 0.6 µg/µL) were associated with neuronal and synaptic toxicity (p<0.01). Markers for gliosis (glial fibrillary acidic protein, GFAP) and microglia (ionized calcium-binding adapter molecule 1, Iba1) were restricted to the needle track and the presence of microglia had diminished by 4 weeks post-infusion. No change in neurite outgrowth (Growth associated protein 43, GAP43, mRNA) compared to artificial cerebral spinal fluid (aCSF) control was observed with any infused concentration.
The results of this study suggest that acute CED of low concentrations of GDNF, with dosing intervals determined by tissue clearance, has most potential for effective clinical translation by optimising distribution and minimising the risk of toxic accumulation.
Url:
DOI: 10.1371/journal.pone.0056186
PubMed: 23526931
PubMed Central: 3603959
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Bristol</wicri:regionArea><wicri:noRegion>Bristol</wicri:noRegion></affiliation></author><author><name sortKey="Wyatt, Marcella" sort="Wyatt, Marcella" uniqKey="Wyatt M" first="Marcella" last="Wyatt">Marcella Wyatt</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>School of Clinical Sciences, University of Bristol, Bristol, United Kingdom</addr-line></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>School of Clinical Sciences, University of Bristol, Bristol</wicri:regionArea><wicri:noRegion>Bristol</wicri:noRegion></affiliation></author><author><name sortKey="Castrique, Emma" sort="Castrique, Emma" uniqKey="Castrique E" first="Emma" last="Castrique">Emma Castrique</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>School of Clinical Sciences, University of Bristol, Bristol, United Kingdom</addr-line></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>School of Clinical Sciences, University of Bristol, Bristol</wicri:regionArea><wicri:noRegion>Bristol</wicri:noRegion></affiliation></author><author><name sortKey="Foster, Rebecca" sort="Foster, Rebecca" uniqKey="Foster R" first="Rebecca" last="Foster">Rebecca Foster</name><affiliation wicri:level="1"><nlm:aff id="aff3"><addr-line>School of Clinical Sciences, University of Bristol, Bristol, United Kingdom</addr-line></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>School of Clinical Sciences, University of Bristol, Bristol</wicri:regionArea><wicri:noRegion>Bristol</wicri:noRegion></affiliation></author><author><name sortKey="Luz, Matthias" sort="Luz, Matthias" uniqKey="Luz M" first="Matthias" last="Luz">Matthias Luz</name><affiliation wicri:level="1"><nlm:aff id="aff4"><addr-line>MedGenesis Therapeutix Inc., Victoria, British Columbia, Canada</addr-line></nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>MedGenesis Therapeutix Inc., Victoria, British Columbia</wicri:regionArea><wicri:noRegion>British Columbia</wicri:noRegion></affiliation></author><author><name sortKey="Fibiger, Christian" sort="Fibiger, Christian" uniqKey="Fibiger C" first="Christian" last="Fibiger">Christian Fibiger</name><affiliation wicri:level="1"><nlm:aff id="aff4"><addr-line>MedGenesis Therapeutix Inc., Victoria, British Columbia, Canada</addr-line></nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>MedGenesis Therapeutix Inc., Victoria, British Columbia</wicri:regionArea><wicri:noRegion>British Columbia</wicri:noRegion></affiliation></author><author><name sortKey="Mohr, Erich" sort="Mohr, Erich" uniqKey="Mohr E" first="Erich" last="Mohr">Erich Mohr</name><affiliation wicri:level="1"><nlm:aff id="aff4"><addr-line>MedGenesis Therapeutix Inc., Victoria, British Columbia, Canada</addr-line></nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>MedGenesis Therapeutix Inc., Victoria, British Columbia</wicri:regionArea><wicri:noRegion>British Columbia</wicri:noRegion></affiliation></author><author><name sortKey="Gill, Steven" sort="Gill, Steven" uniqKey="Gill S" first="Steven" last="Gill">Steven Gill</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>School of Clinical Sciences, University of Bristol, Bristol, United Kingdom</addr-line></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>School of Clinical Sciences, University of Bristol, Bristol</wicri:regionArea><wicri:noRegion>Bristol</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Department of Neurosurgery, Frenchay Hospital, Bristol, United Kingdom</addr-line></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Neurosurgery, Frenchay Hospital, Bristol</wicri:regionArea><wicri:noRegion>Bristol</wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno 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Methionyl Human Glial Cell Line-Derived Neurotrophic Factor (r-metHu GDNF) Following Acute Convection-Enhanced Delivery into the Striatum</title><author><name sortKey="Taylor, Hannah" sort="Taylor, Hannah" uniqKey="Taylor H" first="Hannah" last="Taylor">Hannah Taylor</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>School of Clinical Sciences, University of Bristol, Bristol, United Kingdom</addr-line></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>School of Clinical Sciences, University of Bristol, Bristol</wicri:regionArea><wicri:noRegion>Bristol</wicri:noRegion></affiliation></author><author><name sortKey="Barua, Neil" sort="Barua, Neil" uniqKey="Barua N" first="Neil" last="Barua">Neil Barua</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>School of Clinical Sciences, University of Bristol, Bristol, United Kingdom</addr-line></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>School of Clinical Sciences, University of Bristol, Bristol</wicri:regionArea><wicri:noRegion>Bristol</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Department of Neurosurgery, Frenchay Hospital, Bristol, United Kingdom</addr-line></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Neurosurgery, Frenchay Hospital, Bristol</wicri:regionArea><wicri:noRegion>Bristol</wicri:noRegion></affiliation></author><author><name sortKey="Bienemann, Alison" sort="Bienemann, Alison" uniqKey="Bienemann A" first="Alison" last="Bienemann">Alison Bienemann</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>School of Clinical Sciences, University of Bristol, Bristol, United Kingdom</addr-line></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>School of Clinical Sciences, University of Bristol, Bristol</wicri:regionArea><wicri:noRegion>Bristol</wicri:noRegion></affiliation></author><author><name sortKey="Wyatt, Marcella" sort="Wyatt, Marcella" uniqKey="Wyatt M" first="Marcella" last="Wyatt">Marcella Wyatt</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>School of Clinical Sciences, University of Bristol, Bristol, United Kingdom</addr-line></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>School of Clinical Sciences, University of Bristol, Bristol</wicri:regionArea><wicri:noRegion>Bristol</wicri:noRegion></affiliation></author><author><name sortKey="Castrique, Emma" sort="Castrique, Emma" uniqKey="Castrique E" first="Emma" last="Castrique">Emma Castrique</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>School of Clinical Sciences, University of Bristol, Bristol, United Kingdom</addr-line></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>School of Clinical Sciences, University of Bristol, Bristol</wicri:regionArea><wicri:noRegion>Bristol</wicri:noRegion></affiliation></author><author><name sortKey="Foster, Rebecca" sort="Foster, Rebecca" uniqKey="Foster R" first="Rebecca" last="Foster">Rebecca Foster</name><affiliation wicri:level="1"><nlm:aff id="aff3"><addr-line>School of Clinical Sciences, University of Bristol, Bristol, United Kingdom</addr-line></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>School of Clinical Sciences, University of Bristol, Bristol</wicri:regionArea><wicri:noRegion>Bristol</wicri:noRegion></affiliation></author><author><name sortKey="Luz, Matthias" sort="Luz, Matthias" uniqKey="Luz M" first="Matthias" last="Luz">Matthias Luz</name><affiliation wicri:level="1"><nlm:aff id="aff4"><addr-line>MedGenesis Therapeutix Inc., Victoria, British Columbia, Canada</addr-line></nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>MedGenesis Therapeutix Inc., Victoria, British Columbia</wicri:regionArea><wicri:noRegion>British Columbia</wicri:noRegion></affiliation></author><author><name sortKey="Fibiger, Christian" sort="Fibiger, Christian" uniqKey="Fibiger C" first="Christian" last="Fibiger">Christian Fibiger</name><affiliation wicri:level="1"><nlm:aff id="aff4"><addr-line>MedGenesis Therapeutix Inc., Victoria, British Columbia, Canada</addr-line></nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>MedGenesis Therapeutix Inc., Victoria, British Columbia</wicri:regionArea><wicri:noRegion>British Columbia</wicri:noRegion></affiliation></author><author><name sortKey="Mohr, Erich" sort="Mohr, Erich" uniqKey="Mohr E" first="Erich" last="Mohr">Erich Mohr</name><affiliation wicri:level="1"><nlm:aff id="aff4"><addr-line>MedGenesis Therapeutix Inc., Victoria, British Columbia, Canada</addr-line></nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>MedGenesis Therapeutix Inc., Victoria, British Columbia</wicri:regionArea><wicri:noRegion>British Columbia</wicri:noRegion></affiliation></author><author><name sortKey="Gill, Steven" sort="Gill, Steven" uniqKey="Gill S" first="Steven" last="Gill">Steven Gill</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>School of Clinical Sciences, University of Bristol, Bristol, United Kingdom</addr-line></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>School of Clinical Sciences, University of Bristol, Bristol</wicri:regionArea><wicri:noRegion>Bristol</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Department of Neurosurgery, Frenchay Hospital, Bristol, United Kingdom</addr-line></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Neurosurgery, Frenchay Hospital, Bristol</wicri:regionArea><wicri:noRegion>Bristol</wicri:noRegion></affiliation></author></analytic><series><title level="j">PLoS ONE</title><idno type="eISSN">1932-6203</idno><imprint><date when="2013">2013</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Background</title><p>Despite promising early results, clinical trials involving the continuous delivery of recombinant methionyl human glial cell line-derived neurotrophic factor (r-metHuGDNF) into the putamen for the treatment of Parkinson's disease have shown evidence of poor distribution and toxicity due to point-source accumulation. Convection-enhanced delivery (CED) has the potential to facilitate more widespread and clinically effective drug distribution.</p></sec><sec><title>Aims</title><p>We investigated acute CED of r-metHuGDNF into the striatum of normal rats in order to assess tissue clearance, toxicity (neuron loss, gliosis, microglial activation, and decreases in synaptophysin), synaptogenesis and neurite-outgrowth. We investigated a range of clinically relevant infused concentrations (0.1, 0.2, 0.6 and 1.0 µg/µL) and time points (2 and 4 weeks) in order to rationalise a dosing regimen suitable for clinical translation.</p></sec><sec><title>Results</title><p>Two weeks after single dose CED, r-metHuGDNF was below the limit of detection by ELISA but detectable by immunohistochemistry when infused at low concentrations (0.1 and 0.2 µg/µL). At these concentrations, there was no associated neuronal loss (neuronal nuclei, NeuN, immunohistochemistry) or synaptic toxicity (synaptophysin ELISA). CED at an infused concentration of 0.2 µg/µL was associated with a significant increase in synaptogenesis (p<0.01). In contrast, high concentrations of r-metHuGDNF (above 0.6 µg/µL) were associated with neuronal and synaptic toxicity (p<0.01). Markers for gliosis (glial fibrillary acidic protein, GFAP) and microglia (ionized calcium-binding adapter molecule 1, Iba1) were restricted to the needle track and the presence of microglia had diminished by 4 weeks post-infusion. No change in neurite outgrowth (Growth associated protein 43, GAP43, mRNA) compared to artificial cerebral spinal fluid (aCSF) control was observed with any infused concentration.</p></sec><sec><title>Conclusion</title><p>The results of this study suggest that acute CED of low concentrations of GDNF, with dosing intervals determined by tissue clearance, has most potential for effective clinical translation by optimising distribution and minimising the risk of toxic accumulation.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Lin, Lf" uniqKey="Lin L">LF Lin</name></author><author><name sortKey="Doherty, Dh" uniqKey="Doherty D">DH Doherty</name></author><author><name sortKey="Lile, Jd" uniqKey="Lile J">JD Lile</name></author><author><name sortKey="Bektesh, S" uniqKey="Bektesh S">S Bektesh</name></author><author><name sortKey="Collins, F" uniqKey="Collins F">F 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uniqKey="Woolley M">M Woolley</name></author><author><name sortKey="Castrique, E" uniqKey="Castrique E">E Castrique</name></author><author><name sortKey="Johnson, De" uniqKey="Johnson D">DE Johnson</name></author></analytic></biblStruct></listBibl></div1></back></TEI></record>Pour manipuler ce document sous Unix (Dilib)
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