scholarly journals Assessment of adeno-associated virus gene therapies efficacy on acid alpha-glucosidase restoration and glycogen storage correction in cardiac muscle of Pompe disease mice using synchrotron infrared and ultraviolet microspectroscopies

2019 ◽  
Author(s):  
Laurence Dubreil ◽  
Lydie Lagalice ◽  
Johan Deniaud ◽  
Antoine Sabourin ◽  
Claire Lovo ◽  
...  
Keyword(s):  
High Resolution ◽  
Cardiac Muscle ◽  
Pompe Disease ◽  
Chemical Change ◽  
Glycogen Storage ◽  
Adeno Associated Virus ◽  
Enzyme Replacement ◽  
Virus Serotype ◽  
Stretching Vibrations ◽  
Alpha Glucosidase

Pompe disease (glycogen storage disease type II) is a lysosomal storage disorder due to a mutation in the gene that encodes acid alpha-glucosidase (GAA). GAA deficiency causes the excessive storage of lysosomal glycogen in many cell types, leading to cell and, subsequently, tissue dysfunction. Cardiac, respiratory and skeletal muscles are the most severely affected. Enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA, Myozyme®, Genzyme, Cambridge) is the only approved treatment for Pompe disease. A new therapeutic strategy was developed consisting of delivering adeno-associated virus serotype 9 (AAV9) and serotype 10 (AAV10) vectors expressing human GAA into cerebrospinal fluid of GAA-KO 6neo/6neo Pompe mice. The purpose of this work was to investigate synchrotron Fourier transform infrared (sFT-IR) and deep ultraviolet (sDUV) microspectroscopies to detect new biomarkers of the disease and the AAV gene therapy in the cardiac muscle, one of the most affected organs in Pompe disease. Multivariate statistics applied to sFT-IR spectra between 4000 cm–1 and 950 cm–1 highlighted the potential of sFT-IR to discriminate Pompe (-/-), Wild type and AAV-treated animals from C–H stretching vibrations of CH3, from C–O, C–N and C–C stretching vibrations of amide I, II, III bands and from specific IR signature of the glycogen. Investigations performed by sDUV microscopy showed a significant increase of the tryptophan autofluorescent signal in the right ventricle for the AAV9-treated Pompe mice. The high-resolution sDUV microspectroscopy experiments suggested a correlation between the tryptophan-rich area and the GAA-rich area. These unprecedented results demonstrate that high-resolution UV microspectroscopy can be a complementary innovative approach to monitor the chemical change in label-free cardiac muscle section. Moreover, this non-destructive technology can be applied to a small amount of tissue allowing therapeutic assessment from biopsy of human patients.

scholarly journals Pompe Disease: New Developments in an Old Lysosomal Storage Disorder

Biomolecules ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 1339
Author(s):  
Naresh K. Meena ◽  
Nina Raben
Keyword(s):  
Pompe Disease ◽  
Specific Treatment ◽  
Lysosomal Storage Diseases ◽  
Glycogen Storage Disease Type ◽  
Glycogen Storage ◽  
Lysosomal Storage ◽  
Enzyme Replacement ◽  
Monogenic Diseases ◽  
Progressive Accumulation ◽  
Alpha Glucosidase

Pompe disease, also known as glycogen storage disease type II, is caused by the lack or deficiency of a single enzyme, lysosomal acid alpha-glucosidase, leading to severe cardiac and skeletal muscle myopathy due to progressive accumulation of glycogen. The discovery that acid alpha-glucosidase resides in the lysosome gave rise to the concept of lysosomal storage diseases, and Pompe disease became the first among many monogenic diseases caused by loss of lysosomal enzyme activities. The only disease-specific treatment available for Pompe disease patients is enzyme replacement therapy (ERT) which aims to halt the natural course of the illness. Both the success and limitations of ERT provided novel insights in the pathophysiology of the disease and motivated the scientific community to develop the next generation of therapies that have already progressed to the clinic.

scholarly journals Guidelines for the diagnosis, treatment and clinical monitoring of patients with juvenile and adult Pompe disease

2015 ◽  
Vol 74 (2) ◽  
pp. 166-176 ◽  
Author(s):  
Juan Clinton Llerena Junior ◽  
Osvaldo JM. Nascimento ◽  
Acary Souza B. Oliveira ◽  
Mario Emilio T. Dourado Junior ◽  
Carlo D. Marrone ◽  
...  
Keyword(s):  
Pompe Disease ◽  
Task Force ◽  
Glycogen Storage ◽  
Enzyme Replacement ◽  
Therapeutic Recommendations ◽  
Diagnostic Flowchart ◽  
Monitoring Treatment ◽  
Therapeutic Perspective ◽  
Alpha Glucosidase

ABSTRACT Pompe disease (PD) is a potentially lethal illness involving irreversible muscle damage resulting from glycogen storage in muscle fiber and activation of autophagic pathways. A promising therapeutic perspective for PD is enzyme replacement therapy (ERT) with the human recombinant enzyme acid alpha-glucosidase (Myozyme®). The need to organize a diagnostic flowchart, systematize clinical follow-up, and establish new therapeutic recommendations has become vital, as ERT ensures greater patient longevity. A task force of experienced clinicians outlined a protocol for diagnosis, monitoring, treatment, genetic counseling, and rehabilitation for PD patients. The study was conducted under the coordination of REBREPOM, the Brazilian Network for Studies of PD. The meeting of these experts took place in October 2013, at L’Hotel Port Bay in São Paulo, Brazil. In August 2014, the text was reassessed and updated. Given the rarity of PD and limited high-impact publications, experts submitted their views.

Pompe Disease

2016 ◽  
Author(s):  
Ans T. van der Ploeg ◽  
Pascal Laforêt
Keyword(s):  
Pompe Disease ◽  
Late Onset ◽  
Data Gathering ◽  
Autosomal Recessive Disorder ◽  
Glycogen Storage Disease Type ◽  
Glycogen Storage ◽  
Walking Distance ◽  
Patient Registries ◽  
Enzyme Replacement ◽  
Progressive Muscle Weakness

Pompe disease, also named acid maltase deficiency and glycogen storage disease type II (GSDII), is a rare autosomal recessive disorder caused by the deficiency of the glycogen-degrading lysosomal enzyme acid α‎-glucosidase. The clinical spectrum of this disease is broad, varying from a lethal infantile-onset generalized myopathy including cardiomyopathy, to late-onset slowly progressive muscle weakness mimicking limb-girdle muscular dystrophy. Respiratory insufficiency is a frequent complication and the main cause of death. The prognosis of Pompe disease has changed considerably with the use of enzyme replacement therapy using recombinant acid α‎-glucosidase (alglucosidase alfa), which has been widely available since 2006. Improvements in survival and major motor achievements can be observed in patients with infantile forms, and recent studies demonstrate improvement of walking distance and stabilization of pulmonary function in late-onset forms. A longer-term study of the safety and efficacy of ERT, based on data gathering across the complete spectrum of Pompe disease via national or international patient registries, is needed in order to formulate more precise guidelines for treatment.

Phase I/II Trial of Adeno-associated Virus Acid-alpha-Glucosidase (AAV-GAA) Diaphragm Gene Therapy for Ventilatory Failure in Pompe Disease

2012 ◽  
Vol 105 (2) ◽  
pp. S24
Author(s):  
Barry Byrne ◽  
Barbara Smith ◽  
Anatole Martin ◽  
Cathryn Mah ◽  
Lee Ann Lawson ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Phase I ◽  
Pompe Disease ◽  
Adeno Associated Virus ◽  
Ventilatory Failure ◽  
Alpha Glucosidase

scholarly journals A Systematic Review and Meta-Analysis of Enzyme Replacement Therapy in Late-Onset Pompe Disease

2021 ◽  
Vol 10 (21) ◽  
pp. 4828
Author(s):  
Alícia Dorneles Dornelles ◽  
Ana Paula Pedroso Junges ◽  
Tiago Veiga Pereira ◽  
Bárbara Corrêa Krug ◽  
Candice Beatriz Treter Gonçalves ◽  
...  
Keyword(s):  
Enzyme Replacement Therapy ◽  
Replacement Therapy ◽  
Pompe Disease ◽  
Late Onset ◽  
Meta Analysis ◽  
Glycogen Storage ◽  
Enzyme Replacement ◽  
Sf 36 ◽  
Glycogen Storage Disorder

Pompe disease (PD) is a glycogen storage disorder caused by deficient activity of acid alpha-glucosidase (GAA). We sought to review the latest available evidence on the safety and efficacy of recombinant human GAA enzyme replacement therapy (ERT) for late-onset PD (LOPD). Methods: We systematically searched the MEDLINE (via PubMed), Embase, and Cochrane databases for prospective clinical studies evaluating ERT for LOPD on pre-specified outcomes. A meta-analysis was also performed. Results: Of 1601 articles identified, 22 were included. Studies were heterogeneous and with very low certainty of evidence for most outcomes. The following outcomes showed improvements associated with GAA ERT, over a mean follow-up of 32.5 months: distance walked in the 6-min walking test (6MWT) (mean change 35.7 m (95% confidence interval [CI] 7.78, 63.75)), physical domain of the SF-36 quality of life (QOL) questionnaire (mean change 1.96 (95% CI 0.33, 3.59)), and time on ventilation (TOV) (mean change −2.64 h (95% CI −5.28, 0.00)). There were no differences between the pre- and post-ERT period for functional vital capacity (FVC), Walton and Gardner-Medwin Scale score, upper-limb strength, or total SF-36 QOL score. Adverse events (AEs) after ERT were mild in most cases. Conclusion: Considering the limitations imposed by the rarity of PD, our data suggest that GAA ERT improves 6MWT, physical QOL, and TOV in LOPD patients. ERT was safe in the studied population. PROSPERO register: 135102.

scholarly journals Hepatic expression of GAA results in enhanced enzyme bioavailability in mice and non-human primates

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Helena Costa-Verdera ◽  
Fanny Collaud ◽  
Christopher R. Riling ◽  
Pauline Sellier ◽  
Jayme M. L. Nordin ◽  
...  
Keyword(s):  
Gene Transfer ◽  
Scale Up ◽  
Neuromuscular Disorder ◽  
Adeno Associated Virus ◽  
Peripheral Tissues ◽  
Pharmacological Chaperones ◽  
Enzyme Replacement ◽  
Hepatic Expression ◽  
Alpha Glucosidase

AbstractPompe disease (PD) is a severe neuromuscular disorder caused by deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA). PD is currently treated with enzyme replacement therapy (ERT) with intravenous infusions of recombinant human GAA (rhGAA). Although the introduction of ERT represents a breakthrough in the management of PD, the approach suffers from several shortcomings. Here, we developed a mouse model of PD to compare the efficacy of hepatic gene transfer with adeno-associated virus (AAV) vectors expressing secretable GAA with long-term ERT. Liver expression of GAA results in enhanced pharmacokinetics and uptake of the enzyme in peripheral tissues compared to ERT. Combination of gene transfer with pharmacological chaperones boosts GAA bioavailability, resulting in improved rescue of the PD phenotype. Scale-up of hepatic gene transfer to non-human primates also successfully results in enzyme secretion in blood and uptake in key target tissues, supporting the ongoing clinical translation of the approach.

scholarly journals Newborn Screening for Pompe Disease

2020 ◽  
Vol 6 (2) ◽  
pp. 31
Author(s):  
Takaaki Sawada ◽  
Jun Kido ◽  
Kimitoshi Nakamura
Keyword(s):  
Enzyme Activity ◽  
Newborn Screening ◽  
Pompe Disease ◽  
Autosomal Recessive Disorder ◽  
Glycogen Storage Disease Type ◽  
Dried Blood Spots ◽  
Glycogen Storage ◽  
Glycogen Accumulation ◽  
Enzyme Replacement ◽  
Asian Populations

Glycogen storage disease type II (also known as Pompe disease (PD)) is an autosomal recessive disorder caused by defects in α-glucosidase (AαGlu), resulting in lysosomal glycogen accumulation in skeletal and heart muscles. Accumulation and tissue damage rates depend on residual enzyme activity. Enzyme replacement therapy (ERT) should be started before symptoms are apparent in order to achieve optimal outcomes. Early initiation of ERT in infantile-onset PD improves survival, reduces the need for ventilation, results in earlier independent walking, and enhances patient quality of life. Newborn screening (NBS) is the optimal approach for early diagnosis and treatment of PD. In NBS for PD, measurement of AαGlu enzyme activity in dried blood spots (DBSs) is conducted using fluorometry, tandem mass spectrometry, or digital microfluidic fluorometry. The presence of pseudodeficiency alleles, which are frequent in Asian populations, interferes with NBS for PD, and current NBS systems cannot discriminate between pseudodeficiency and cases with PD or potential PD. The combination of GAA gene analysis with NBS is essential for definitive diagnoses of PD. In this review, we introduce our experiences and discuss NBS programs for PD implemented in various countries.

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