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E - Disease Models and Clinical Applications -> Neurologic Diseases (Excluding Ophthalmic and Auditory Diseases)

6: Midbrain Gene Therapy for AADC Deficiency

Type: Clinical

Presentation Details
Session Title: Clinical Trials Spotlight Symposium
Location: Concourse Hall 152 & 153
Start Time: 5/18/2023 8:30
End Time: 5/18/2023 8:45

OBJECTIVEAromatic L-amino acid decarboxylase (AADC) deficiency is a neurodevelopmental disorder characterized by congenital deficiency of dopamine and serotonin. It presents in infancy with hypotonia, hypokinesia, oculogyric crises (OGC), dystonia, autonomic dysfunction, and global developmental delay. Here we describe interim findings from a Phase 1/2 dose escalation trial to evaluate the tolerability of MR-guided delivery of adeno-associated virus serotype 2 (AAV2)-hAADC to the bilateral midbrain in children and young adults with AADC deficiency.
METHODSTwenty-eight individuals (15F, 13M; median age 8.0 years, range 4-27 years) received AAV2-AADC (dose 4.2 x 1011-1.5 x 1012 vector genomes(vg)) delivered in a single infusion of up to 300 microliters per hemisphere, targeting the substantia nigra pars compacta and ventral tegmental area. Changes in symptoms and motor function were assessed by caregiver log, neurologic examination and systematic review of home videos for attainment of motor milestones. Changes in dopamine metabolism were assessed by analysis of CSF homovanillic acid (HVA).
RESULTSResults were analyzed for 17 subjects who were followed for at least 12 months (range: 12-45 months). OGC improved in all subjects and resolved completely in 14/17 (82%) after gene delivery. All subjects had severe motor function impairment at baseline, with inability to sit without support. Motor function improvement was observed across the age spectrum. By 12 months post-surgery, head control was attained by 16/17 (94%) of subjects, and independent sitting by 80% (4/5) under age 7 years and 42% (5/12) age 7 years or older at time of surgery. Two subjects (baseline ages 4.8, 4.9 years) walked independently by 36 months. All subjects experienced improvements in mood, sleep, and feeding tolerance. CSF HVA increased from <20% of the lower limit of normal at baseline, to 24-100% at 6-12 months post-gene transfer (median increase 87 nmol/L, range 30-190), consistent with increased brain dopamine synthesis. All subjects tolerated the surgical procedure well. Post-treatment dyskinesia was experienced by all subjects, peaking between 6 and 12 weeks after surgery and improving over 6-12 months.
CONCLUSIONSMidbrain AAV2-AADC gene delivery has now been performed in a total of 35 individuals. The procedure is safe and produces consistent and sustained improvements for up to 5 years in oculogyric crises, mood, sleep, and motor function in patients with AADC deficiency.

Krystof Bankiewicz1,2,3, Toni Pearson4, Malgorzata Kohutnicka5, Waldy San Sebastian2, Dora Steel6, Robert Spaull6, Audrey Soo6, Simon Heales6, Roser Pons7, Angeles Garcia-Cazorla8, Salvador Ibanez-Mico9, Jolanta Sykut-Cegielska10, Krystyna Szymanska10, Thomas Opladen11, Kathrin Jeltsch11, Mari Oppeboen12, Herve Testard13, Anne Roscher14, Sandy Siegert14, Michèl Willemsen15, Saadet Andrews16, Bruria Ben-Zeev17, Manju Kurian6, Miroslaw Zabek5

1The Ohio State University, Columbus, OH,2University of California San Francisco, San Francisco, CA,3Interventional Neuro Center, Warsaw, Poland,4Nationwide Children's Hospital, Columbus, OH,5Interventional Neuro Center, Brodno Hospital, Warsaw, Poland,6University College London, London, United Kingdom,7University of Athens, Athens, Greece,8San Joan de Deu Hospital, Barcelona, Spain,9Arrixaca Universitary Hospital, Murcia, Spain,10Institute of Mother and Child, Warsaw, Poland,11Heidelberg University Hospital, Heidelberg, Germany,12Oslo University Hospital, Oslo, Norway,13Centre Hospital Alpes, Contamine Sur Arve, France,14Medical University Hospital Vienna, Vienna, Austria,15Radboud University Medical Center, Nijmegen, Netherlands,16University of Toronto, Toronto, ON, Canada,17Sheba Medical Center, Tel Aviv, Israel
 K. Bankiewicz: None.

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