Kojima K, Nakajima T, Taga N, Miyauchi A, Kato M, Matsumoto A, Ikeda T, Nakamura K, Kubota T, Mizukami H, Ono S, Onuki Y, Sato T, Osaka H, Muramatsu SI, Yamagata T. Gene therapy improves motor and mental function of aromatic l-amino acid decarboxylase deficiency. Brain. 2019 Feb 1;142(2):322-333.
In patients with aromatic l-amino acid decarboxylase (AADC) deficiency, a decrease in catecholamines and serotonin levels in the brain leads to developmental delay and movement disorders. The beneficial effects of gene therapy in patients from 1 to 8 years of age with homogeneous severity of disease have been reported from Taiwan. We conducted an open-label phase 1/2 study of population including adolescent patients with different degrees of severity. Six patients were enrolled: four males (ages 4, 10, 15 and 19 years) and one female (age 12 years) with a severe phenotype who were not capable of voluntary movement or speech, and one female (age 5 years) with a moderate phenotype who could walk with support. The patients received a total of 2 × 1011 vector genomes of adeno-associated virus vector harbouring DDC via bilateral intraputaminal infusions. At up to 2 years after gene therapy, the motor function was remarkably improved in all patients. Three patients with the severe phenotype were able to stand with support, and one patient could walk with a walker, while the patient with the moderate phenotype could run and ride a bicycle. This moderate-phenotype patient also showed improvement in her mental function, being able to converse fluently and perform simple arithmetic. Dystonia disappeared and oculogyric crisis was markedly decreased in all patients. The patients exhibited transient choreic dyskinesia for a couple of months, but no adverse events caused by vector were observed. PET with 6-[18F]fluoro-l-m-tyrosine, a specific tracer for AADC, showed a persistently increased uptake in the broad areas of the putamen. In our study, older patients (>8 years of age) also showed improvement, although treatment was more effective in younger patients. The genetic background of our patients was heterogeneous, and some patients suspected of having remnant enzyme activity showed better improvement than the Taiwanese patients. In addition to the alleviation of motor symptoms, the cognitive and verbal functions were improved in a patient with the moderate phenotype. The restoration of dopamine synthesis in the putamen via gene transfer provides transformative medical benefit across all patient ages, genotypes, and disease severities included in this study, with the most pronounced improvements noted in moderate patients.
Chien YH, Lee NC, Tseng SH, Tai CH, Muramatsu SI, Byrne BJ, Hwu WL. 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 Dec;1(4):265-273.
Aromatic l-amino acid decarboxylase (AADC) deficiency is an inherited disease that causes depletion of neurotransmitters and severe motor dysfunction in infants and children. We previously reported compassionate use of an adeno-associated virus (AAV) vector containing the human AADC gene (AAV2-hAADC) in four children with AADC deficiency (aged 4-6 years). In this study, we aimed to establish the efficacy and safety of this treatment.
We did an open-label, phase 1/2 trial at the National Taiwan University Hospital (Taipei, Taiwan). We included patients who had a definitive diagnosis and clinical symptoms of AADC deficiency (hypotonia, dystonia, and oculogyric crisis), who were older than 24 months or had skull bones suitable for stereotactic surgery, and who had an anti-AAV2 antibody titre lower than 1·0 optical density. All patients received bilateral intraputaminal injections of AAV2-hAADC (1·81 × 1011 vg in total) through stereotactic brain surgery. Primary efficacy outcomes were an increase in the Peabody Developmental Motor Scales (second edition; PDMS-2) score of greater than 10 points and an increase in homovanillic acid (HVA) or 5-hydroxyindoleacetic acid (5-HIAA) concentrations in the cerebrospinal fluid 12 months after gene therapy. We assessed patients at baseline and at 3, 6, 9, and 12 months after gene therapy, and every 6 months thereafter for one further year; all patients who received the treatment were included in the analysis. We assessed for surgical complications (cerebrospinal fluid leakage and intracerebral haemorrhage) at days 3-7 after AAV2 gene therapy, and we assessed adverse events during the follow-up evaluations for 12 months. This study is registered with ClinicalTrials.gov, number NCT01395641.
Ten patients (median age 2·71 years, IQR 2·46-6·35) were enrolled from Oct 1, 2014, to Dec 2, 2015. All patients tolerated the surgeries and vector injections. One patient died from influenza B encephalitis during an endemic outbreak 10 months after treatment; therefore, 9 months of data were included in the analyses for this patient. All patients met the primary efficacy endpoint: 12 months after gene therapy, PDMS-2 scores were increased by a median of 62 points (IQR 39-93; p=0·005) and HVA concentrations by a median of 25 nmol/L (IQR 11-48; p=0·012); however, there was no significant change in 5-HIAA concentrations (median difference 0, IQR 0-5; p=0·20). In total, 101 adverse events were reported, with the most common being pyrexia (16 [16%] of 101 events) and orofacial dyskinesia (ten [10%]). 12 serious adverse events occurred in six patients, including one death (treatment-unrelated encephalitis due to influenza B infection), one life-threatening pyrexia, and ten events that led to hospital admission. Transient post-gene therapy dyskinesia occurred in all patients but was resolved with risperidone. Of 31 treatment-related adverse events, only one (patient 1) was severe in intensity, and none led to hospital admission or death.
Our findings suggest that intraputaminal injection of AAV2-hAADC is well tolerated and might improve motor development in children with AADC deficiency.