Intraputaminal Gene Delivery in Two Patients with Aromatic L‐Amino Acid Decarboxylase Deficiency

Abstract

Background Aromatic l‐amino acid decarboxylase deficiency (AADCD) is a rare, early‐onset, dyskinetic encephalopathy mostly reflecting a defective synthesis of brain dopamine and serotonin. Intracerebral gene delivery (GD) provided a significant improvement among AADCD patients (mean age, ≤6 years). Objective We describe the clinical, biological, and imaging evolution of two AADCD patients ages >10 years after GD. Methods Eladocagene exuparvovec, a recombinant adeno‐associated virus containing the human complimentary DNA encoding the AADC enzyme, was administered into bilateral putamen by stereotactic surgery. Results Eighteen months after GD, patients showed improvement in motor, cognitive and behavioral function, and in quality of life. Cerebral l‐6‐[18F] fluoro‐3, 4‐dihydroxyphenylalanine uptake was increased at 1 month, persisting at 1 year compared to baseline. Conclusion Two patients with a severe form of AADCD had an objective motor and non‐motor benefit from eladocagene exuparvovec injection even when treated after the age of 10 years, as in the seminal study.

Gene therapy for neurotransmitter‐related disorders

“…69 Lately, motor and non-motor improvements 1-year posttreatment were reported in two older patients (treated when >10 years old) with severe AADCD, with improved putaminal 18 F-DOPA uptake compared to baseline. 72 Similar results were shown in a Japanese Phase 1/2 rAAV2 study also using CMV promoter, showing significant putaminal AADC activity detected by PET, improved motor functions (AIMS), and reduced OGC duration up to 2 years post-gene therapy in severe AADCD patients. 73 The gene therapy was administered at a higher concentration (i.e., lower infusion volume of 50 μL/site, with a similar total dose of 2 Â 10 11 vg).…”

“…Any DA agonists or monoamine oxide inhibitors may be tapered and weaned off, as necessary 77,159 . Agents such as amantadine, benzodiazepines, gabapentin, clonidine or even tetrabenazine may be considered for the short‐term management of this transient dyskinesia 72,79 . Some patients will need more intensive medical management within intensive care or high dependency.…”

“…Dyskinesia onset within 3 months of treatment, was relieved by risperidone and resolved by 10 months; severity and duration correlated with age of patients rather than dosage 69 . Lately, motor and non‐motor improvements 1‐year post‐treatment were reported in two older patients (treated when >10 years old) with severe AADCD, with improved putaminal 18 F‐DOPA uptake compared to baseline 72 …”

Patient selection considerations for AADC deficiency gene therapy

“…No serious adverse events were reported during the procedure or follow-up period. 12 An open-label phase 1/2 study in Japan examined another rAAV2-hAADC construct, delivered into the putamina of six patients, aged 4-19 years at the time of treatment. 13 These patients had varying degrees of impairment.…”

“…6,11 The symptomatic presentation of AADC deficiency is varied; whereas some patients may have subtle clinical presentations, others have profound impairment. 2,8,[12][13][14][15] Until recently, treatment options for AADC deficiency offered partial symptomatic improvement either by maintaining existing monoamine levels through catabolic inhibition or by mimicking endogenous monoaminemediated signal effects with receptor agonists. 2,10,11 However, these treatments are of limited efficacy in many patients and do not address the underlying cause of the disease.…”