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SAFETY AND TOLERABILITY OF MRI-GUIDED INFUSION OF AAV2-hAADC INTO THE MID-BRAIN OF NON-HUMAN PRIMATE.

San Sebastian W, Kells AP, Bringas J, Samaranch L, Hadaczek P, Ciesielska A, Macayan M, Pivirotto PJ, Forsayeth J, Osborne S, Wright JF, Green F, Heller G, Bankiewicz KS - Mol Ther Methods Clin Dev (2014)

Bottom Line: As a result, patients suffer compromised development, particularly in motor function.The objective of this study was to assess the long-term safety and tolerability of bilateral AAV2-hAADC MRI-guided pressurized infusion into the mid-brain of non-human primates.Our data indicate that effective mid-brain transduction was achieved without untoward effects.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.

ABSTRACT

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare, autosomal-recessive neurological disorder caused by mutations in the DDC gene that leads to an inability to synthesize catecholamines and serotonin. As a result, patients suffer compromised development, particularly in motor function. A recent gene replacement clinical trial explored putaminal delivery of recombinant adeno-associated virus serotype 2 vector encoding human AADC (AAV2-hAADC) in AADC-deficient children. Unfortunately, patients presented only modest amelioration of motor symptoms, which authors acknowledged could be due to insufficient transduction of putamen. We hypothesize that, with the development of a highly accurate MRI-guided cannula placement technology, a more effective approach might be to target the affected mid-brain neurons directly. Transduction of AADC-deficient dopaminergic neurons in the substantia nigra and ventral tegmental area with locally infused AAV2-hAADC would be expected to lead to restoration of normal dopamine levels in affected children. The objective of this study was to assess the long-term safety and tolerability of bilateral AAV2-hAADC MRI-guided pressurized infusion into the mid-brain of non-human primates. Animals received either vehicle, low or high AAV2-hAADC vector dose and were euthanized 1, 3 or 9 months after surgery. Our data indicate that effective mid-brain transduction was achieved without untoward effects.

No MeSH data available.


Related in: MedlinePlus

Reproducibility of magnetic resonance (MR) image-guided infusion of AAV2-hAADC into the primate mid-brain. Top panel shows representative coronal MR images of AAV2-hAADC after pressure-driven delivery in each animal. Please note there was slight reflux in only 2 out of 36 infusion performed (V002458 and V002254). Summary table below presents diffusion volume/infusion volume ratio (Vd/Vi, mean ± SD) for pilot and toxicology groups.
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fig1: Reproducibility of magnetic resonance (MR) image-guided infusion of AAV2-hAADC into the primate mid-brain. Top panel shows representative coronal MR images of AAV2-hAADC after pressure-driven delivery in each animal. Please note there was slight reflux in only 2 out of 36 infusion performed (V002458 and V002254). Summary table below presents diffusion volume/infusion volume ratio (Vd/Vi, mean ± SD) for pilot and toxicology groups.

Mentions: In both studies, AAV2-hAADC (N = 14) or vehicle (N = 4) was used to infuse the right and left SNpc and VTA (total of 36 cannula insertions). Up to 46 μl of the infusate per hemisphere was infused bilaterally (30 μl per side in the toxicology study). Gadolinium-enhanced magnetic resonance images (MRI) from each infusion confirmed that positioning of each cannula was accurate and infusate covered the target area (Figure 1). All of the 36 infusions were well contained in the target structure with slight reflux seen along the cannula tract in only two cases (Figure 1: V002458, left side; V002254, right side). Three-dimensional reconstructions of the infusate distribution generated from gadolinium signal on MR images showed that both placement and distribution of infusate were very consistent throughout all the animals (Supplementary Figure S1). As well, the ratio (Vd/Vi) between volume of distribution (Vd) and volume of infusion (Vi) was calculated for each delivery and data were consistent across infusions in both studies. Vd was approximately twofold larger than the Vi (pilot study: 2.23 ± 0.24; toxicology study: 2.18 ± 0.52; Figure 1 and Supplementary Table S1). No MRI-visible hemorrhages occurred during cannula placement and no adverse events occurred during infusion or subsequently.


SAFETY AND TOLERABILITY OF MRI-GUIDED INFUSION OF AAV2-hAADC INTO THE MID-BRAIN OF NON-HUMAN PRIMATE.

San Sebastian W, Kells AP, Bringas J, Samaranch L, Hadaczek P, Ciesielska A, Macayan M, Pivirotto PJ, Forsayeth J, Osborne S, Wright JF, Green F, Heller G, Bankiewicz KS - Mol Ther Methods Clin Dev (2014)

Reproducibility of magnetic resonance (MR) image-guided infusion of AAV2-hAADC into the primate mid-brain. Top panel shows representative coronal MR images of AAV2-hAADC after pressure-driven delivery in each animal. Please note there was slight reflux in only 2 out of 36 infusion performed (V002458 and V002254). Summary table below presents diffusion volume/infusion volume ratio (Vd/Vi, mean ± SD) for pilot and toxicology groups.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4274790&req=5

fig1: Reproducibility of magnetic resonance (MR) image-guided infusion of AAV2-hAADC into the primate mid-brain. Top panel shows representative coronal MR images of AAV2-hAADC after pressure-driven delivery in each animal. Please note there was slight reflux in only 2 out of 36 infusion performed (V002458 and V002254). Summary table below presents diffusion volume/infusion volume ratio (Vd/Vi, mean ± SD) for pilot and toxicology groups.
Mentions: In both studies, AAV2-hAADC (N = 14) or vehicle (N = 4) was used to infuse the right and left SNpc and VTA (total of 36 cannula insertions). Up to 46 μl of the infusate per hemisphere was infused bilaterally (30 μl per side in the toxicology study). Gadolinium-enhanced magnetic resonance images (MRI) from each infusion confirmed that positioning of each cannula was accurate and infusate covered the target area (Figure 1). All of the 36 infusions were well contained in the target structure with slight reflux seen along the cannula tract in only two cases (Figure 1: V002458, left side; V002254, right side). Three-dimensional reconstructions of the infusate distribution generated from gadolinium signal on MR images showed that both placement and distribution of infusate were very consistent throughout all the animals (Supplementary Figure S1). As well, the ratio (Vd/Vi) between volume of distribution (Vd) and volume of infusion (Vi) was calculated for each delivery and data were consistent across infusions in both studies. Vd was approximately twofold larger than the Vi (pilot study: 2.23 ± 0.24; toxicology study: 2.18 ± 0.52; Figure 1 and Supplementary Table S1). No MRI-visible hemorrhages occurred during cannula placement and no adverse events occurred during infusion or subsequently.

Bottom Line: As a result, patients suffer compromised development, particularly in motor function.The objective of this study was to assess the long-term safety and tolerability of bilateral AAV2-hAADC MRI-guided pressurized infusion into the mid-brain of non-human primates.Our data indicate that effective mid-brain transduction was achieved without untoward effects.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.

ABSTRACT

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare, autosomal-recessive neurological disorder caused by mutations in the DDC gene that leads to an inability to synthesize catecholamines and serotonin. As a result, patients suffer compromised development, particularly in motor function. A recent gene replacement clinical trial explored putaminal delivery of recombinant adeno-associated virus serotype 2 vector encoding human AADC (AAV2-hAADC) in AADC-deficient children. Unfortunately, patients presented only modest amelioration of motor symptoms, which authors acknowledged could be due to insufficient transduction of putamen. We hypothesize that, with the development of a highly accurate MRI-guided cannula placement technology, a more effective approach might be to target the affected mid-brain neurons directly. Transduction of AADC-deficient dopaminergic neurons in the substantia nigra and ventral tegmental area with locally infused AAV2-hAADC would be expected to lead to restoration of normal dopamine levels in affected children. The objective of this study was to assess the long-term safety and tolerability of bilateral AAV2-hAADC MRI-guided pressurized infusion into the mid-brain of non-human primates. Animals received either vehicle, low or high AAV2-hAADC vector dose and were euthanized 1, 3 or 9 months after surgery. Our data indicate that effective mid-brain transduction was achieved without untoward effects.

No MeSH data available.


Related in: MedlinePlus