Gene therapy for aromatic L-amino acid decarboxylase deficiency by MR-guided direct delivery of AAV2-AADC to midbrain dopaminergic neurons

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.

Breakthrough News in Adenoviral Vector‐Mediated AADC Gene Therapy: Lessons from the Success in AADC Deficiency and Possible Future Applications

“…Since the first clinical trial, 31 PD and 20 AADC-def patients received intrastriatal/ intraputaminal AAV2-hADDC infusion, which is deemed safe and effective. 1,2 Pearson and colleagues 4 first investigated AAV2-hADDC delivery to midbrain regions (ie, SNpc and ventral tegmental area) in seven AADC-def cases. Unlike PD, AADC-def is characterized by intact midbrain dopaminergic neurons (including their efferent projections), and anterograde axonal transport to downstream brain structures (eg, striatum) is therefore preserved.…”

Advances in brain barriers and brain fluids research in 2021: great progress in a time of adversity

“…Although progress is being made in therapeutic delivery from blood to brain, direct intracerebral delivery is still being investigated, with for example, use of convection-enhanced delivery to increase the dispersion of the therapeutic. Thus, Pearson et al [ 154 ] used convection-enhanced delivery of adeno-associated virus 2 to deliver the gene for the enzyme aromatic L-amino acid decarboxylase. This approach was used to deliver the vector to the midbrain of children with enzyme deficiency resulting in improvements in function 12–18 months after gene delivery.…”

Towards Precision Therapies for Inherited Disorders of Neurodegeneration with Brain Iron Accumulation

“…AAV vector-mediated delivery of functional genes is potentially an attractive option for a number of NBIA disorders in that this approach can restore gene expression in loss-of-function recessive disorders, and targeted putaminal and midbrain AAV9 delivery is already established [ 11 10 ]. To date, gene replacement therapy using an AAV vector has been administered in plag2g6-inad mice in the neonatal period prior to onset of symptoms, and was successful in rescuing motor symptoms and neuropathological features [ 118 ].…”

“…Indeed, in recent years, previously untreatable childhood-onset neurogenetic conditions have had their first treatments licensed. These include cerliponase alfa enzyme replacement therapy for ceroid lipofuscinosis type 2 (late infantile Batten disease) [ 8 ], advances in spinal muscular atrophy treatment with the antisense oligonucleotide treatment nusinersen [ 9 ], and targeted gene therapy for aromatic L-amino acid decarboxylase (AADC) deficiency [ 10 11 ]. At present there are no proven disease-modifying precision treatments for the NBIA disorders.…”