Benefits of Neuronal Preferential Systemic Gene Therapy for Neurotransmitter Deficiency

Lee, Ni‐Chung; Muramatsu, Shin‐ichi; Chien, Yin‐Hsiu; Liu, Wen-Shin; Cheng, Chia-Hao; Hu, Meng-Kai; Chen, Pin-Wen; Tzen, Kai-Yuan; Byrne, Barry J.; Hwu, Wuh‐Liang

doi:10.1038/mt.2015.122

Cited by 25 publications

(24 citation statements)

References 24 publications

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“…Due to concerns that this hyperactivity may have been due to excess ectopic DA production and the invasive procedure in the neonatal period, we modified our viral vector delivery strategy to use intraperitoneal injection of the neuronal preferential viral vector (yfAAV9/3‐Syn‐I‐mAADC) in 7‐day‐old DDC KI mice (Lee et al, ). The yfAAV9/3‐Syn‐I‐mAADC‐treated mice showed greater neuronal transduction, higher brain DA level and less hyperactivity compared with AAV9‐CMV‐hAADC‐treated mice (Lee et al, ). Further large animal experiments are in progress to develop the next generation of gene therapies for patients with AADCD.…”

Section: Developing Other Therapeutic Strategiesmentioning

confidence: 99%

A review of aromatic l‐amino acid decarboxylase (AADC) deficiency in Taiwan

Lee

Chien

Hwu

2019

American J of Med Genetics Pt C

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Aromatic l‐amino acid decarboxylase deficiency (AADCD) is a rare inherited disease prevalent in South East Asia. This disease is due to the founder mutation IVS 6 + 4A > T (c.714 + 4A > T), which accounts for most alleles. Patients with this mutation have severe phenotypes. About 90 % of these patients in South East Asia do not have head control and cannot sit, stand, or speak from birth to the time of observation. In 2012, a gene study to treat these patients with intraputamen injection of adeno‐associated virus2‐human AADC showed prominent motor improvement and an increased PDMS‐2 score 12 months after treatment. In addition, systemic gene therapy in a mouse model of AADCD achieved widespread correction of the Ddc gene. In this article, we review the natural history, clinical course, and treatment effects seen in these clinical and mouse studies. Future studies focusing on noninvasive viral vector delivery or alternative emerging treatments may also benefit patients with AADCD.

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Section: Developing Other Therapeutic Strategiesmentioning

confidence: 99%

A review of aromatic l‐amino acid decarboxylase (AADC) deficiency in Taiwan

Lee

Chien

Hwu

2019

American J of Med Genetics Pt C

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“…We previously demonstrated that Ddc KI (KI) mice exhibit a profound DA deficiency, poor weight gain, and early death (Lee et al, 2013); possibly due to reduced food intake and followed by essential compounds deficiency including tryptophan that further worsen the serotonin deficiency; and gene therapy rescues these deficits (Lee et al, 2014, 2015). Gene therapy-treated and untreated mice were used in the present study.…”

Section: Resultsmentioning

confidence: 99%

“…One possible reason for the restoration may be associated with an increment in dopamine level in the brain. Furthermore, we have previously reported that gene therapy is effective and improves motor function in patient and mouse with AADC deficiency (Hwu et al, 2012; Lee et al, 2014, 2015). These results suggest that replenished dopamine level in the brain by gene therapy restored motor function and cellular homeostasis in AADC deficiency.…”

Section: Discussionmentioning

confidence: 99%

“…A neuron-specific virus (yfAAV9/3-Syn-I-mAADC; AAVN-AADC) with a viral titer of 2.3 × 10 13 vg/ml was bilaterally injected into the lateral ventricles [intracerebroventricular (ICV) injection; 2 × 10 10 vg in 2 μl for each hemisphere] of neonatal Ddc KI mice (<24 h; P0) as previously described (Kim et al, 2013; Lee et al, 2014). Analyses of DA and serotonin levels in mouse half brain homogenates were performed by high performance liquid chromatography (HPLC) as previously described methods (Lee et al, 2015). Dual IF staining was performed on 30 μm coronal sections.…”

Section: Methodsmentioning

confidence: 99%

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Electrical Abnormalities in Dopaminergic Neurons of the Substantia Nigra in Mice With an Aromatic L-Amino Acid Decarboxylase Deficiency

Chien

Tsai

et al. 2019

Front. Cell. Neurosci.

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Aromatic L-acid decarboxylase (AADC) deficiency causes severe motor disturbances in affected children. A putamen-targeted gene therapy improves the motor function of patients. The present study investigated the electrical properties of dopaminergic (DA) neurons in the substantia nigra compacta (SNc) of mice with an AADC deficiency (DdcKI). The basal firing of DA neurons, which determines DA release in the putamen, was abnormal in the DdcKI mice, including a low frequency and irregular firing pattern, because of a decrease in the after-hyperpolarization (AHP) amplitude of action potentials (APs). The frequency of spontaneous excitatory postsynaptic currents (sEPSCs) increased and that of spontaneous inhibitory PSCs (sIPSCs) decreased in the SNc DA neurons from the DdcKI mice, suggesting an elevation in glutamatergic excitatory stimuli and a reduction in GABAergic inhibitory stimuli, respectively. Altered expression patterns of genes encoding receptors and channels were also observed in the DdcKI mice. Administration of a widespread neuron-specific gene therapy to the brains of the DdcKI mice partially corrected these electric abnormalities. The overexcitability of SNc DA neurons in the presence of generalized dopamine deficiency likely underlies the occurrence of motor disturbances.

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“…In a recent clinical trial (#NCT01395641) of AADC deficiency, Hwu et al directly injected AAV2 vector carrying AADC gene into the bilateral putamen of four 4- to 6-year-old patients. 78 , 79 All subjects were reported to gain weight after 3 to 6 months post-gene transfer and had better head control and emotional stability. Importantly, their Alberta Infant Motor Scale, Peabody Developmental Motor Scale, and Comprehensive Developmental Inventory for Infants and Toddlers scores were better after 15 to 24 months of gene therapy, indicating improvement in their motor and cognitive functions.…”

Section: Inherited Neurological Disordersmentioning

confidence: 98%

Clinical development of gene therapy: results and lessons from recent successes

Kumar

Markusic

Biswas

et al. 2016

Molecular Therapy - Methods & Clinical Development

199

138

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Therapeutic gene transfer holds the promise of providing lasting therapies and even cures for diseases that were previously untreatable or for which only temporary or suboptimal treatments were available. For some time, clinical gene therapy was characterized by some impressive but rare examples of successes and also several setbacks. However, effective and long-lasting treatments are now being reported from gene therapy trials at an increasing pace. Positive outcomes have been documented for a wide range of genetic diseases (including hematological, immunological, ocular, and neurodegenerative and metabolic disorders) and several types of cancer. Examples include restoration of vision in blind patients, eradication of blood cancers for which all other treatments had failed, correction of hemoglobinopathies and coagulation factor deficiencies, and restoration of the immune system in children born with primary immune deficiency. To date, about 2,000 clinical trials for various diseases have occurred or are in progress, and many more are in the pipeline. Multiple clinical studies reported successful treatments of pediatric patients. Design of gene therapy vectors and their clinical development are advancing rapidly. This article reviews some of the major successes in clinical gene therapy of recent years.

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Benefits of Neuronal Preferential Systemic Gene Therapy for Neurotransmitter Deficiency

Cited by 25 publications

References 24 publications

A review of aromatic l‐amino acid decarboxylase (AADC) deficiency in Taiwan

A review of aromatic l‐amino acid decarboxylase (AADC) deficiency in Taiwan

Electrical Abnormalities in Dopaminergic Neurons of the Substantia Nigra in Mice With an Aromatic L-Amino Acid Decarboxylase Deficiency

Clinical development of gene therapy: results and lessons from recent successes

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