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.
Abstract
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.
Abstract
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.
METHODS:
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.
FINDINGS:
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.
INTERPRETATION:
Our findings suggest that intraputaminal injection of
AAV2-hAADC is well tolerated and might improve motor development in children
with AADC deficiency.
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