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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

Surgery and vector-related histological findings. Independent evaluation of hematoxylin and eosin (H&E) staining of coronal sections containing the cannula tract revealed normal gliosis related to cannula insertion in all experimental groups (arrowheads). Higher magnification images (right column) were taken close to the cannula tip (black arrows in left column). H&E staining also showed perivascular cellular infiltrates in AAV2-hAADC-treated, but not PBS-treated, animals regardless of survival time. Although incidence and severity of perivascular cuffs was increased with AAV2-hAADC vector dose, these were not considered adverse. Note that there were also many vessels with no perivascular cuffing close to the infusion site (white arrows in left column) and that perivascular cellular infiltrates were not present in the pilot AAV2-hAADC animal. Scale bars: left column: 1 cm; right column: 100 μm.
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fig2: Surgery and vector-related histological findings. Independent evaluation of hematoxylin and eosin (H&E) staining of coronal sections containing the cannula tract revealed normal gliosis related to cannula insertion in all experimental groups (arrowheads). Higher magnification images (right column) were taken close to the cannula tip (black arrows in left column). H&E staining also showed perivascular cellular infiltrates in AAV2-hAADC-treated, but not PBS-treated, animals regardless of survival time. Although incidence and severity of perivascular cuffs was increased with AAV2-hAADC vector dose, these were not considered adverse. Note that there were also many vessels with no perivascular cuffing close to the infusion site (white arrows in left column) and that perivascular cellular infiltrates were not present in the pilot AAV2-hAADC animal. Scale bars: left column: 1 cm; right column: 100 μm.

Mentions: Hematoxylin and eosin (H&E) staining of the infusion site in pilot animals demonstrated some gliosis located only around the cannula tract (Figure 2). Similarly, an independent histopathology report on toxicological study animals revealed vacuolated macrophages and gliosis attributable to the infusion procedure itself, because it was present in both control and AAV2-hAADC-treated groups (low- or high-dose) either 1, 3, or 9 months after infusion. Gliosis was less commonly observed at 9 months than at 1 or 3 months and was considered evidence of partial resolution of the damage associated with the infusion procedure. Also, independent histopathological assessment in the toxicology study showed the presence of perivascular mononuclear cell infiltrates only in animals receiving AAV2-hAADC infusion at either low- or high-dose. Nevertheless, they were not considered adverse since animals displayed no symptomatology associated with it. In addition, there were no pathological findings related to infusion with the test article in either the spinal cord or major organ tissues.


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)

Surgery and vector-related histological findings. Independent evaluation of hematoxylin and eosin (H&E) staining of coronal sections containing the cannula tract revealed normal gliosis related to cannula insertion in all experimental groups (arrowheads). Higher magnification images (right column) were taken close to the cannula tip (black arrows in left column). H&E staining also showed perivascular cellular infiltrates in AAV2-hAADC-treated, but not PBS-treated, animals regardless of survival time. Although incidence and severity of perivascular cuffs was increased with AAV2-hAADC vector dose, these were not considered adverse. Note that there were also many vessels with no perivascular cuffing close to the infusion site (white arrows in left column) and that perivascular cellular infiltrates were not present in the pilot AAV2-hAADC animal. Scale bars: left column: 1 cm; right column: 100 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig2: Surgery and vector-related histological findings. Independent evaluation of hematoxylin and eosin (H&E) staining of coronal sections containing the cannula tract revealed normal gliosis related to cannula insertion in all experimental groups (arrowheads). Higher magnification images (right column) were taken close to the cannula tip (black arrows in left column). H&E staining also showed perivascular cellular infiltrates in AAV2-hAADC-treated, but not PBS-treated, animals regardless of survival time. Although incidence and severity of perivascular cuffs was increased with AAV2-hAADC vector dose, these were not considered adverse. Note that there were also many vessels with no perivascular cuffing close to the infusion site (white arrows in left column) and that perivascular cellular infiltrates were not present in the pilot AAV2-hAADC animal. Scale bars: left column: 1 cm; right column: 100 μm.
Mentions: Hematoxylin and eosin (H&E) staining of the infusion site in pilot animals demonstrated some gliosis located only around the cannula tract (Figure 2). Similarly, an independent histopathology report on toxicological study animals revealed vacuolated macrophages and gliosis attributable to the infusion procedure itself, because it was present in both control and AAV2-hAADC-treated groups (low- or high-dose) either 1, 3, or 9 months after infusion. Gliosis was less commonly observed at 9 months than at 1 or 3 months and was considered evidence of partial resolution of the damage associated with the infusion procedure. Also, independent histopathological assessment in the toxicology study showed the presence of perivascular mononuclear cell infiltrates only in animals receiving AAV2-hAADC infusion at either low- or high-dose. Nevertheless, they were not considered adverse since animals displayed no symptomatology associated with it. In addition, there were no pathological findings related to infusion with the test article in either the spinal cord or major organ tissues.

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