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      Systemic Treatment of Fabry Disease Using a Novel AAV9 Vector Expressing α-Galactosidase A

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          Abstract

          Fabry disease is a rare X-linked disorder affecting α-galactosidase A, a rate-limiting enzyme in lysosomal catabolism of glycosphingolipids. Current treatments present important limitations, such as low half-life and limited distribution, which gene therapy can overcome. The aim of this work was to test a novel adeno-associated viral vector, serotype 9 (AAV9), ubiquitously expressing human α-galactosidase A to treat Fabry disease (scAAV9-PGK-GLA). The vector was preliminary tested in newborns of a Fabry disease mouse model. 5 months after treatment, α-galactosidase A activity was detectable in the analyzed tissues, including the central nervous system. Moreover, we tested the vector in adult animals of both sexes at two doses and disease stages (presymptomatic and symptomatic) by single intravenous injection. We found that the exogenous α-galactosidase A was active in peripheral tissues as well as the central nervous system and prevented glycosphingolipid accumulation in treated animals up to 5 months following injection. Antibodies against α-galactosidase A were produced in 9 out of 32 treated animals, although enzyme activity in tissues was not significantly affected. These results demonstrate that scAAV9-PGK-GLA can drive widespread and sustained expression of α-galactosidase A, cross the blood brain barrier after systemic delivery, and reduce pathological signs of the Fabry disease mouse model.

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          Abstract

          This study focuses on the development of a novel gene therapy vector for Fabry disease (FD). The approach is based on the systemic delivery of an AAV9, which crosses the blood brain barrier and drives sustained expression of α-galactosidase A, reducing pathological signs in multiple organs of a FD mouse model, including the central nervous system.

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          Most cited references 51

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          Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy

          Spinal muscular atrophy type 1 (SMA1) is a progressive, monogenic motor neuron disease with an onset during infancy that results in failure to achieve motor milestones and in death or the need for mechanical ventilation by 2 years of age. We studied functional replacement of the mutated gene encoding survival motor neuron 1 (SMN1) in this disease.
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            Emerging Issues in AAV-Mediated In Vivo Gene Therapy

            In recent years, the number of clinical trials in which adeno-associated virus (AAV) vectors have been used for in vivo gene transfer has steadily increased. The excellent safety profile, together with the high efficiency of transduction of a broad range of target tissues, has established AAV vectors as the platform of choice for in vivo gene therapy. Successful application of the AAV technology has also been achieved in the clinic for a variety of conditions, including coagulation disorders, inherited blindness, and neurodegenerative diseases, among others. Clinical translation of novel and effective “therapeutic products” is, however, a long process that involves several cycles of iterations from bench to bedside that are required to address issues encountered during drug development. For the AAV vector gene transfer technology, several hurdles have emerged in both preclinical studies and clinical trials; addressing these issues will allow in the future to expand the scope of AAV gene transfer as a therapeutic modality for a variety of human diseases. In this review, we will give an overview on the biology of AAV vector, discuss the design of AAV-based gene therapy strategies for in vivo applications, and present key achievements and emerging issues in the field. We will use the liver as a model target tissue for gene transfer based on the large amount of data available from preclinical and clinical studies.
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              Stroke in Fabry disease frequently occurs before diagnosis and in the absence of other clinical events: natural history data from the Fabry Registry.

              Stroke is a common and serious clinical manifestation of Fabry disease, an X-linked lysosomal storage disorder caused by deficiency of alpha-galactosidase A activity. This study was undertaken to better understand the natural history of cerebrovascular manifestations of Fabry disease. Data from 2446 patients in the Fabry Registry were analyzed to identify clinical characteristics of patients experiencing stroke during the natural history period (ie, before enzyme replacement therapy). A total of 138 patients (86 of 1243 males [6.9%] and 52 of 1203 females [4.3%]) experienced strokes. Median age at first stroke was 39.0 years in males and 45.7 years in females. Most patients (70.9% of males and 76.9% of females) had not experienced renal or cardiac events before their first stroke. Fifty percent of males and 38.3% of females experienced their first stroke before being diagnosed with Fabry disease. Thirty patients (21 males and 9 females) had strokes at age <30 years. Most patients (86.8%) had ischemic strokes, but 16.9% of males and 6.9% of females had hemorrhagic strokes, among those for whom stroke type was reported. At the most recently available follow-up examination after their first stroke, 60% of males and 25.5% of females exhibited stage 3 to 5 chronic kidney disease and 66.1% of males and 59.5% of females had left ventricular hypertrophy. All patients with Fabry disease, regardless of age or gender, should be monitored for possible cerebrovascular complications, as stroke can occur in the absence of other key signs of the disease.
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                Author and article information

                Contributors
                Journal
                Mol Ther Methods Clin Dev
                Mol Ther Methods Clin Dev
                Molecular Therapy. Methods & Clinical Development
                American Society of Gene & Cell Therapy
                2329-0501
                22 October 2020
                12 March 2021
                22 October 2020
                : 20
                : 1-17
                Affiliations
                [1 ]Sorbonne Université, INSERM, Institute of Myology, Centre of Research in Myology, 75013 Paris, France
                [2 ]Rare Diseases and Pediatric Medicine Research Group, Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO, Hospital Álvaro Cunqueiro, 36312 Vigo, Spain
                [3 ]Bioexperimentation Service of the University of Vigo (Sbio), Campus Universitario Lagoas, Marcosende, 36310 Vigo, Spain
                [4 ]CINBIO, Centro de Investigaciones Biomédicas, Universidade de Vigo, Immunology Group, Campus Universitario Lagoas, Marcosende, 36310 Vigo, Spain
                [5 ]Immunology Group, Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO, Vigo, Spain
                Author notes
                []Corresponding author Saida Ortolano, PhD, Rare Diseases and Pediatric Medicine, Galicia Sur Health Research Institute, Hospital Álvaro Cunqueiro, Bloque Tecnico, Planta 2 A, Estrada Clara Campoamor 341, 36312 Vigo (Pontevedra), Spain. saida.ortolano@ 123456iisgaliciasur.es
                Article
                S2329-0501(20)30220-5
                10.1016/j.omtm.2020.10.016
                7725667
                © 2020 The Author(s)

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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