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

Abstract

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.

Ultrastructural and diffusion tensor imaging studies reveal axon abnormalities in Pompe disease mice

“…Once the estimated duty cycle was under 40%, DTI imaging parameters we set were acceptable to scan rodent brains. The diffusion MRI data was acquired using a single-shot spin-echo echo-planar-imaging sequence with following parameters: TR/TE = 6750 ms/34.5 ms, FOV = 20 × 20 mm 2 , matrix = 75 × 75, 22 axial slices with 0.267 mm thickness, averages = 10, flip angle = 90°, in-plane resolution = 267 × 267 μm 2 , b-values for 42 diffusion gradient directions (1 b0/41 directions) = 0/1000 s/mm 2 , diffusion gradient duration (δ) = 2.112 ms; diffusion gradient separation (Δ) = 25.699 ms 31 . To quantify the thickness of the corpus callosum, we measured the thickness of the genu at the midline on one axial slice that best delineated the genu.…”

A Proposed Diagnostic Algorithm for Inborn Errors of Metabolism Presenting With Movements Disorders

“…Keeping up to date with the emergence of new gene therapies is essential. Gene therapy trials using viral vectors results in improvement of MD and motor function in early clinical studies of AADC deficiency (150,151). Kojima et al, conducted an open-label phase 1/2 study including six patients whom received adeno-associated virus vector harboring DDC via bilateral intraputaminal infusions.…”

“…As an adverse effect, transient chorea was observed (150). Tseng et al, demonstrated that there was an improvement in the microstructural integrity of white matter tracts using Brain diffusion tensor imaging (DTI) 1 year after AADC gene therapy (151).…”

High throughput newborn screening for aromatic ʟ‐amino‐acid decarboxylase deficiency by analysis of concentrations of 3‐O‐methyldopa from dried blood spots

“…The International Working Group on Neurotransmitter related Disorders (iNTD) published a consensus guideline on drug treatment recommendations for AADC deficiency; nevertheless, treatment options are not considered as disease‐changing . Recent clinical trials evaluating DDC gene replacement therapy using an adeno‐associated virus vector (AAV2‐hAADC) bilaterally administered to the putamen or substantia nigra showed sustained improvement of motor and cognitive functions and accompanying neuroradiologic and neurometabolic changes . Positive treatment outcomes correlated with early, pre‐symptomatic diagnosis and treatment initiation, emphasising the need for early and reliable diagnostic approaches, for example, in newborn screening (NBS) .…”

“…2,4 Recent clinical trials evaluating DDC gene replacement therapy using an adeno-associated virus vector (AAV2-hAADC) bilaterally administered to the putamen or substantia nigra showed sustained improvement of motor and cognitive functions and accompanying neuroradiologic and neurometabolic changes. [5][6][7] Positive treatment outcomes correlated with early, pre-symptomatic diagnosis and treatment initiation, emphasising the need for early and reliable diagnostic approaches, for example, in newborn screening (NBS). 6,7 3-OMD concentration is increased in dried blood spots of AADC deficient patients, and hence is a candidate biomarker for NBS.…”