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

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.

SUBMITTER: San Sebastian W

PROVIDER: S-EPMC4274790 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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

San Sebastian Waldy W Kells Adrian P AP Bringas John J Samaranch Lluis L Hadaczek Piotr P Ciesielska Agnieszka A Macayan Michael M Pivirotto Phillip J PJ Forsayeth John J Osborne Sheryl S Wright J Fraser JF Green Foad F Heller Gregory G Bankiewicz Krystof S KS

Molecular therapy. Methods & clinical development 20141001

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare, autosomal-recessive neurological disorder caused by mutations in the <i>DDC</i> 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. Unfortu ...[more]

PMID: 25541617

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Project description:Background and aimInfliximab is typically given over an infusion time of 2 hours, leading to a significant burden in inflammatory bowel disease (IBD) patients. We aimed to determine the safety and cost-effectiveness of an accelerated infliximab infusion of 1 hour, compared with the standard 2-hour infusion.MethodsOpen-label randomized trial where IBD patients receiving maintenance infliximab infusions were randomly assigned to 1- and 2-hour infusion groups, corresponding to study and control groups, respectively. The primary outcome was the rate of infusion reactions. Secondary outcomes were assessment of the effect of premedications and immunomodulators on the rate of infusion reactions, and cost-effectiveness analysis. The cost-effectiveness analysis was based on direct nursing costs for the infusion time, indirect infusion center costs, and cost of productivity loss for patients. This trial is registered with ClinicalTrials.gov, NCT05340764.ResultsFrom November 2020 to November 2021, 96 patients were randomly assigned: 51 (53%) to the 1-hour infusion group and 45 (47%) to the 2-hour infusion group. Over a median time of 1 year, 309 infusions were administered in the control group, and 376 in the study group. Fifty-seven (18%) infusions in the control group and 45 (12%) infusions in the study group experienced an infusion reaction. The only infusion reaction was asymptomatic hypotension not requiring infusion discontinuation. No other infusion reactions (mild or moderate/severe) were seen. Diphenhydramine was associated with an increased rate of infusion reactions (OR 2.04 [95% CI 1.18-3.52], P = .01). The average costs were estimated to reduce by 37% in the accelerated infusion group.ConclusionsAccelerated 1-hour infusions are non-inferior in safety and superior in cost-effectiveness compared with standard 2-hour infusions in IBD patients receiving maintenance infliximab infusions.Trial identification numberRegistered with ClinicalTrials.gov, NCT05340764.

Dataset Information

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

Publications

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

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