Efficacy and safety of AAV2 gene therapy in children with aromatic L-amino acid decarboxylase deficiency: an open-label, phase 1/2 trial

Chien, Yin‐Hsiu; Lee, Ni‐Chung; Tseng, Sheng-Hong; Tai, Chun‐Hwei; Muramatsu, Shin‐ichi; Byrne, Barry J.; Hwu, Wuh‐Liang

doi:10.1016/s2352-4642(17)30125-6

Cited by 111 publications

(135 citation statements)

References 26 publications

Supporting

Mentioning

128

Contrasting

Order By: Relevance

“…Genetic therapies, now available for severe and untreatable disorders, such as AADC deficiency and neuronal ceroid lipofuscinosis types 2 and 6, will be implemented in the future to cover further conditions for which a disease‐modifying approach is not available. Most likely a number of conditions reported here will continue to be treated with a traditional medical approach, as they already have a treatment able to change their natural history if started in the early or asymptomatic phases.…”

Section: Conclusive Remarksmentioning

confidence: 99%

Treatable Inherited Movement Disorders in Children: Spotlight on Clinical and Biochemical Features

Galosi

Nardecchia

Leuzzi

2020

Movement Disord Clin Pract

View full text Add to dashboard Cite

Background About 80% of monogenic metabolic diseases causing movement disorders (MDs) emerges during the first 2 decades of life, and a number of these conditions offers the opportunity of a disease‐modifying treatment. The implementation of enlarged neonatal screening programs and the impressive rapid increase of the identification of new conditions are enhancing our potential to recognize and treat several diseases causing MDs, changing their outcome and phenotypic spectrum. Methods and Findings A literature review of monogenic disorders causing MDs amenable to treatment was conducted focusing on early clinical signs and diagnostic biomarkers. A classification in 3 broad categories based on the therapeutic approach has been proposed. Some disorders result in irreversible neurotoxic lesions that can only be prevented if treated in a presymptomatic stage, and others present with a progressive neurological impairment that a timely diagnosis and treatment may reverse or improve. Some MDs are the result of the failure of intracellular energy supply or altered glucose transport. The treatment in these conditions includes vitamins or a metabolic shift from a carbohydrate to a fatty acid catabolism, respectively. Finally, a group of highly treatable MDs are the result of defects of neurotransmitter metabolism. In these disorders, the supplementation of precursors or mimetics of neurotransmitters can deeply change the disease natural history. Conclusions To prevent serious and irreversible neurological impairment, the diagnostic work‐up of MDs in children should consider a number of clinical red flags and biomarkers denoting specifically treatable diseases.

show abstract

Section: Conclusive Remarksmentioning

confidence: 99%

Treatable Inherited Movement Disorders in Children: Spotlight on Clinical and Biochemical Features

Galosi

Nardecchia

Leuzzi

2020

Movement Disord Clin Pract

View full text Add to dashboard Cite

show abstract

“…The patients who received gene therapy have been described previously, 15,16 except for patient 4 who received the treatment as compassionate use. The patients who received gene therapy have been described previously, 15,16 except for patient 4 who received the treatment as compassionate use.…”

Section: Study Design and Participantsmentioning

confidence: 99%

“…Intraputaminal injection of an AADC-expressing adeno-associated viral (AAV) vector 11 was first attempted as a gene therapy for Parkinson's disease, which is caused by degeneration of dopaminergic neurons in the substantia nigra. 15,16 In our phase I/II openlabel trial, 10 patients (aged 1.7-8.4 years) were treated by bilateral intraputaminal injection of the AAV2-hAADC vector. 15,16 In our phase I/II openlabel trial, 10 patients (aged 1.7-8.4 years) were treated by bilateral intraputaminal injection of the AAV2-hAADC vector.…”

mentioning

confidence: 99%

Gene therapy improves brain white matter in aromatic l‐amino acid decarboxylase deficiency

Tseng

Chien

Lee

et al. 2019

Annals of Neurology

View full text Add to dashboard Cite

Objective: Children with aromatic L-amino acid decarboxylase (AADC) deficiency suffer from severe motor dysfunction. Restoration of dopamine levels in the putamen by gene therapy has led to significant improvement in motor function. This study explored brain structure changes in patients. Methods: Brain diffusion tensor imaging (DTI) was performed before and 12 months after gene therapy. Whole-brain tract-specific analysis was performed to assess white matter microstructural integrity. Results: In the 8 patients (aged 1.67-8.42 years) enrolled in the study, gene therapy did not affect macroscopic structure. DTI before gene therapy revealed lower total mean fractional anisotropy (FA) values in patients than in the age-matched pretreatment controls (p = 0.017; median difference = −0.0136; 95% confidence interval [CI] [−0.0319, −0.0126]). After gene therapy, total mean FA increased (p = 0.012, median difference = 0.0211, 95% CI [0.0094, 0.0456]), and the values in the patients were not different from the age-matched posttreatment controls. Increase in total mean FA after gene therapy in patients was correlated with their increase in motor score (r = 0.846; p = 0.008), but was inversely correlated with their ages at the time of gene therapy (r = −0.754; p = 0.031). Corticospinal tracts, and the thalamic radiation and callosal fibers involving motor function, improved after gene therapy. Interpretation: Improvement in the microstructural integrity of white matter tracts is associated with the improvement in motor function following gene therapy.

show abstract

Section: Disease‐modifying and Disease‐specific Therapiesmentioning

confidence: 99%

“…Gene therapy trials using viral vectors are now in extension phases with promising results in improvement of movement disorder and motor function in early clinical studies of AADC deficiency. 55 In some other monogenic disorders, better understanding of disease mechanisms has led to trials of interventions that target disease mechanisms. An example is the use of JAK inhibitors or reverse-transcriptase inhibitors trialled in Aicardi-Goutieres syndrome presenting with progressive dystonia and progressive spinal paraplegia, which target cellular processes, and preliminary data suggest reduced disease activity.…”

Section: Gene Therapy and Other Disease-modifying Therapiesmentioning

confidence: 99%

Current therapies and therapeutic decision making for childhood‐onset movement disorders

2019

View full text Add to dashboard Cite

Movement disorders differ in children to adults. First, neurodevelopmental movement disorders such as tics and stereotypies are more prevalent than parkinsonism, and second, there is a genomic revolution which is now explaining many early‐onset dystonic syndromes. We outline an approach to children with movement disorders starting with defining the movement phenomenology, determining the level of functional impairment due to abnormal movements, and screening for comorbid psychiatric conditions and cognitive impairments which often contribute more to disability than the movements themselves. The rapid improvement in our understanding of the etiology of movement disorders has resulted in an increasing focus on precision medicine, targeting treatable conditions and defining modifiable disease processes. We profile some of the key disease‐modifying therapies in metabolic, neurotransmitter, inflammatory, and autoimmune conditions and the increasing focus on gene or cellular therapies. When no disease‐modifying therapies are possible, symptomatic therapies are often all that is available. These classically target dopaminergic, cholinergic, alpha‐adrenergic, or GABAergic neurochemistry. Increasing interest in neuromodulation has highlighted that some clinical syndromes respond better to DBS, and further highlights the importance of “disease‐specific” therapies with a future focus on individualized therapies according to the genomic findings or disease pathways that are disrupted. We summarize some pragmatic applications of symptomatic therapies, neuromodulation techniques, and some rehabilitative interventions and provide a contemporary overview of treatment in childhood‐onset movement disorders. © 2019 International Parkinson and Movement Disorder Society

show abstract

Efficacy and safety of AAV2 gene therapy in children with aromatic L-amino acid decarboxylase deficiency: an open-label, phase 1/2 trial

Abstract: AADC Research Fund at National Taiwan University Hospital and the National Research Programme for Biopharmaceuticals.

Cited by 111 publications

References 26 publications

Treatable Inherited Movement Disorders in Children: Spotlight on Clinical and Biochemical Features

Treatable Inherited Movement Disorders in Children: Spotlight on Clinical and Biochemical Features

Gene therapy improves brain white matter in aromatic l‐amino acid decarboxylase deficiency

Current therapies and therapeutic decision making for childhood‐onset movement disorders

Contact Info

Product

Resources

About