Gene therapy for aromatic L-amino acid decarboxylase deficiency by MR-guided direct delivery of AAV2-AADC to midbrain dopaminergic neurons
Toni S Pearson, Nalin Gupta, Waldy San Sebastian, Jill Imamura-Ching, Amy Viehoever, Ana Grijalvo-Perez, Alex J Fay, Neha Seth, Shannon M Lundy, Youngho Seo, Miguel Pampaloni, Keith Hyland, Erin Smith, Gardenia de Oliveira Barbosa, Jill C Heathcock, Amy Minnema, Russell Lonser, J Bradley Elder, Jeffrey Leonard, Paul Larson, Krystof S Bankiewicz, Toni S Pearson, Nalin Gupta, Waldy San Sebastian, Jill Imamura-Ching, Amy Viehoever, Ana Grijalvo-Perez, Alex J Fay, Neha Seth, Shannon M Lundy, Youngho Seo, Miguel Pampaloni, Keith Hyland, Erin Smith, Gardenia de Oliveira Barbosa, Jill C Heathcock, Amy Minnema, Russell Lonser, J Bradley Elder, Jeffrey Leonard, Paul Larson, Krystof S Bankiewicz
Abstract
Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare genetic disorder characterized by deficient synthesis of dopamine and serotonin. It presents in early infancy, and causes severe developmental disability and lifelong motor, behavioral, and autonomic symptoms including oculogyric crises (OGC), sleep disorder, and mood disturbance. We investigated the safety and efficacy of delivery of a viral vector expressing AADC (AAV2-hAADC) to the midbrain in children with AADC deficiency (ClinicalTrials.gov Identifier NCT02852213). Seven (7) children, aged 4-9 years underwent convection-enhanced delivery (CED) of AAV2-hAADC to the bilateral substantia nigra (SN) and ventral tegmental area (VTA) (total infusion volume: 80 µL per hemisphere) in 2 dose cohorts: 1.3 × 1011 vg (n = 3), and 4.2 × 1011 vg (n = 4). Primary aims were to demonstrate the safety of the procedure and document biomarker evidence of restoration of brain AADC activity. Secondary aims were to assess clinical improvement in symptoms and motor function. Direct bilateral infusion of AAV2-hAADC was safe, well-tolerated and achieved target coverage of 98% and 70% of the SN and VTA, respectively. Dopamine metabolism was increased in all subjects and FDOPA uptake was enhanced within the midbrain and the striatum. OGC resolved completely in 6 of 7 subjects by Month 3 post-surgery. Twelve (12) months after surgery, 6/7 subjects gained normal head control and 4/7 could sit independently. At 18 months, 2 subjects could walk with 2-hand support. Both the primary and secondary endpoints of the study were met. Midbrain gene delivery in children with AADC deficiency is feasible and safe, and leads to clinical improvements in symptoms and motor function.
Conflict of interest statement
N.G. reports relationships with Oscine Therapeutics (consulting) and Y-mAbs Therapeutics (consulting). K.H. reports that he is employed by Medical Neurogenetics Laboratories, a company that provides commercial diagnostic testing for aromatic l-amino acid decarboxylase deficiency. P.L. reports relationships with Axovant (Advisory Board), Neurocrine Biosciences (research funding, consulting), UniQure (research funding), Voyager Therapeutics (research funding), and Clearpoint Neuro (consulting). K.S.B. is the founder and equity holder of Brain Neurotherapy Bio. The remaining authors have no competing interests to disclose.
© 2021. The Author(s).
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References
- Hyland K, Clayton PT. Aromatic amino acid decarboxylase deficiency in twins. J. Inherit. Metab. Dis. 1990;13:301–304. doi: 10.1007/BF01799380.
- Wassenberg T, et al. Consensus guideline for the diagnosis and treatment of aromatic l-amino acid decarboxylase (AADC) deficiency. Orphanet J. Rare Dis. 2017;12:12. doi: 10.1186/s13023-016-0522-z.
- Brun L, et al. Clinical and biochemical features of aromatic L-amino acid decarboxylase deficiency. Neurology. 2010;75:64–71. doi: 10.1212/WNL.0b013e3181e620ae.
- Pearson, T. S. et al. AADC deficiency from infancy to adulthood: symptoms and developmental outcome in an international cohort of 63 patients. J. Inherit. Metab. Dis. (2020) 10.1002/jimd.12247.
- Hwu, W. L., Chien, Y. H., Lee, N. C. & Li, M. H. Natural history of aromatic L-amino acid decarboxylase deficiency in Taiwan. JIMD Rep. (2017) 10.1007/8904_2017_54.
- Limousin P, Foltynie T. Long-term outcomes of deep brain stimulation in Parkinson disease. Nat. Rev. Neurol. 2019;15:234–242. doi: 10.1038/s41582-019-0145-9.
- Parmar M, Grealish S, Henchcliffe C. The future of stem cell therapies for Parkinson disease. Nat. Rev. Neurosci. 2020;21:103–115. doi: 10.1038/s41583-019-0257-7.
- Hitti FL, Yang AI, Gonzalez-Alegre P, Baltuch GH. Human gene therapy approaches for the treatment of Parkinson’s disease: an overview of current and completed clinical trials. Parkinsonism Relat. Disord. 2019;66:16–24. doi: 10.1016/j.parkreldis.2019.07.018.
- Kordower JH, et al. Delivery of neurturin by AAV2 (CERE-120)-mediated gene transfer provides structural and functional neuroprotection and neurorestoration in MPTP-treated monkeys. Ann. Neurol. 2006;60:706–715. doi: 10.1002/ana.21032.
- Heiss JD, et al. Trial of magnetic resonance-guided putaminal gene therapy for advanced Parkinson’s disease. Mov. Disord. 2019;34:1073–1078. doi: 10.1002/mds.27724.
- Christine CW, et al. Safety and tolerability of putaminal AADC gene therapy for Parkinson disease. Neurology. 2009;73:1662–1669. doi: 10.1212/WNL.0b013e3181c29356.
- Christine CW, et al. Magnetic resonance imaging-guided phase 1 trial of putaminal AADC gene therapy for Parkinson’s disease. Ann. Neurol. 2019;85:704–714. doi: 10.1002/ana.25450.
- Bankiewicz KS, et al. Convection-enhanced delivery of AAV vector in parkinsonian monkeys; in vivo detection of gene expression and restoration of dopaminergic function using pro-drug approach. Exp. Neurol. 2000;164:2–14. doi: 10.1006/exnr.2000.7408.
- Lee WT, Weng WC, Peng SF, Tzen KY. Neuroimaging findings in children with paediatric neurotransmitter diseases. J. Inherit. Metab. Dis. 2009;32:361–370. doi: 10.1007/s10545-009-1106-z.
- Hwu WL, et al. Gene therapy for aromatic L-amino acid decarboxylase deficiency. Sci. Transl. Med. 2012;4:134ra61. doi: 10.1126/scitranslmed.3003640.
- Chien Y-H, et al. Efficacy and safety of AAV2 gene therapy in children with aromatic L-amino acid decarboxylase deficiency: an open-label, phase 1/2 trial. Lancet Child Adolesc. Health. 2017;1:265–273. doi: 10.1016/S2352-4642(17)30125-6.
- Kojima K, et al. Gene therapy improves motor and mental function of aromatic l-amino acid decarboxylase deficiency. Brain J. Neurol. 2019;142:322–333. doi: 10.1093/brain/awy331.
- Kells AP, et al. Efficient gene therapy-based method for the delivery of therapeutics to primate cortex. Proc. Natl Acad. Sci. USA. 2009;106:2407–2411. doi: 10.1073/pnas.0810682106.
- San Sebastian, W. et al. Safety and tolerability of MRI-guided infusion of AAV2-hAADC into the mid-brain of non-human primate. Mol. Ther. Methods Clin. Dev. 3, 14049 (2014).
- Richardson RM, et al. Interventional MRI-guided putaminal delivery of AAV2-GDNF for a planned clinical trial in Parkinson’s disease. Mol. Ther. 2011;19:1048–1057. doi: 10.1038/mt.2011.11.
- Richardson RM, et al. Novel platform for MRI-guided convection-enhanced delivery of therapeutics: preclinical validation in nonhuman primate brain. Stereotact. Funct. Neurosurg. 2011;89:141–151. doi: 10.1159/000323544.
- Richardson RM, et al. T2 imaging in monitoring of intraparenchymal real-time convection-enhanced delivery. Neurosurgery. 2011;69:154–163. doi: 10.1227/NEU.0b013e318217217e.
- Su X, et al. Real-time MR imaging with Gadoteridol predicts distribution of transgenes after convection-enhanced delivery of AAV2 vectors. Mol. Ther. J. Am. Soc. Gene Ther. 2010;18:1490–1495. doi: 10.1038/mt.2010.114.
- Yin D, et al. Cannula placement for effective convection-enhanced delivery in the nonhuman primate thalamus and brainstem: implications for clinical delivery of therapeutics. J. Neurosurg. 2010;113:240–248. doi: 10.3171/2010.2.JNS091744.
- Russell DJ, et al. The gross motor function measure: a means to evaluate the effects of physical therapy. Dev. Med. Child Neurol. 1989;31:341–352. doi: 10.1111/j.1469-8749.1989.tb04003.x.
- Matsuda W, et al. Single nigrostriatal dopaminergic neurons form widely spread and highly dense axonal arborizations in the neostriatum. J. Neurosci. J. Soc. Neurosci. 2009;29:444–453. doi: 10.1523/JNEUROSCI.4029-08.2009.
- Muramatsu S, et al. A phase I study of aromatic L-amino acid decarboxylase gene therapy for Parkinson’s disease. Mol. Ther. J. Am. Soc. Gene Ther. 2010;18:1731–1735. doi: 10.1038/mt.2010.135.
- Hadaczek P, et al. Eight years of clinical improvement in MPTP-lesioned primates after gene therapy with AAV2-hAADC. Mol. Ther. J. Am. Soc. Gene Ther. 2010;18:1458–1461. doi: 10.1038/mt.2010.106.
- Sehara Y, et al. Persistent expression of dopamine-synthesizing enzymes 15 years after gene transfer in a primate model of Parkinson’s disease. Hum. Gene Ther. Clin. Dev. 2017;28:74–79. doi: 10.1089/humc.2017.010.
- Mittermeyer G, et al. Long-term evaluation of a phase 1 study of AADC gene therapy for Parkinson’s disease. Hum. Gene Ther. 2012;23:377–381. doi: 10.1089/hum.2011.220.
- Sparrow, S., Cicchetti, D. & Balla, D. Vineland Adaptive Behavior Scales, Survey Interview Form/Caregiver Rating Form (Pearson Assessments, 2005).
- Hyland K, et al. Cerebrospinal fluid concentrations of pterins and metabolites of serotonin and dopamine in a pediatric reference population. Pediatr. Res. 1993;34:10–14. doi: 10.1203/00006450-199307000-00003.
- Hyland K, Clayton PT. Aromatic L-amino acid decarboxylase deficiency: diagnostic methodology. Clin. Chem. 1992;38:2405–2410. doi: 10.1093/clinchem/38.12.2405.
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