scholarly journals Rescue of Pompe disease in mice by AAV-mediated liver delivery of secretable acid α-glucosidase

2017 ◽  
Vol 9 (418) ◽  
pp. eaam6375 ◽  
Author(s):  
Francesco Puzzo ◽  
Pasqualina Colella ◽  
Maria G. Biferi ◽  
Deeksha Bali ◽  
Nicole K. Paulk ◽  
...  
Keyword(s):  
Pompe Disease ◽  
Therapeutic Potential ◽  
Scale Up ◽  
Glycogen Storage Disease Type ◽  
Neuromuscular Disorder ◽  
The Body ◽  
Respiratory Dysfunction ◽  
Glycogen Accumulation ◽  
Enzyme Replacement ◽  
Hepatic Expression

Glycogen storage disease type II or Pompe disease is a severe neuromuscular disorder caused by mutations in the lysosomal enzyme, acid α-glucosidase (GAA), which result in pathological accumulation of glycogen throughout the body. Enzyme replacement therapy is available for Pompe disease; however, it has limited efficacy, has high immunogenicity, and fails to correct pathological glycogen accumulation in nervous tissue and skeletal muscle. Using bioinformatics analysis and protein engineering, we developed transgenes encoding GAA that could be expressed and secreted by hepatocytes. Then, we used adeno-associated virus (AAV) vectors optimized for hepatic expression to deliver the GAA transgenes to Gaa knockout (Gaa−/−) mice, a model of Pompe disease. Therapeutic gene transfer to the liver rescued glycogen accumulation in muscle and the central nervous system, and ameliorated cardiac hypertrophy as well as muscle and respiratory dysfunction in the Gaa−/− mice; mouse survival was also increased. Secretable GAA showed improved therapeutic efficacy and lower immunogenicity compared to nonengineered GAA. Scale-up to nonhuman primates, and modeling of GAA expression in primary human hepatocytes using hepatotropic AAV vectors, demonstrated the therapeutic potential of AAV vector–mediated liver expression of secretable GAA for treating pathological glycogen accumulation in multiple tissues in Pompe disease.

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.

scholarly journals Screening of Chimeric GAA Variants in a Preclinical Study of Pompe Disease Results in Candidate Vector for Hematopoietic Stem Cell Gene Therapy

2021 ◽  
Author(s):  
Yildirim Dogan ◽  
Cecilia N. Barese ◽  
Jeffrey W. Schindler ◽  
John K. Yoon ◽  
Zeenath Unnisa ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Mouse Model ◽  
Pompe Disease ◽  
Lentiviral Vector ◽  
Therapeutic Potential ◽  
Neuromuscular Disorder ◽  
Current Standard ◽  
Hematopoietic Stem ◽  
Coding Sequences ◽  
Enzyme Replacement

Pompe disease is a rare genetic neuromuscular disorder caused by acid alpha-glucosidase (GAA) deficiency resulting in lysosomal glycogen accumulation and progressive myopathy. Enzyme replacement therapy (ERT) is the current standard of care, which prolongs the quality of life for Pompe patients. However, ERT has limitations due to lack of enzyme penetration into the central nervous system (CNS) and skeletal muscles, immunogenicity against the recombinant enzyme, and requires life-long biweekly infusions. In a preclinical mouse model, a clinically relevant promoter to drive lentiviral vector-mediated expression of engineered GAA in autologous hematopoietic stem and progenitor cells (HSPC) was tested with nine unique human chimeric GAA coding sequences incorporating distinct peptide tags and codon-optimization iterations. Vectors including glycosylation independent lysosomal targeting (GILT) tags resulted in effective GAA enzyme delivery into key disease tissues with enhanced reduction of glycogen, myofiber and CNS vacuolation, compared to non-tagged GAA in Gaa knockout mice, a model of Pompe disease. Genetically modified microglial cells in brains were detected at low levels, but provided robust correction. Furthermore, an aminoacid substitution in the tag added to reduced capacity to induce insulin signaling and there was no evidence of off-target effects. This study demonstrated the therapeutic potential of lentiviral HSPC gene therapy exploiting optimized GAA tagged coding sequences to reverse Pompe disease pathology in a preclinical mouse model providing a promising vector candidate for further investigation.

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.

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.

scholarly journals The Respiratory Phenotype of Pompe Disease Rodent Models

2020 ◽  
Author(s):  
Anna Fusco ◽  
Angela McCall ◽  
Justin Dhindsa ◽  
Lucy Zheng ◽  
Aidan Bailey ◽  
...  
Keyword(s):  
Pompe Disease ◽  
Neuromuscular Junctions ◽  
Respiratory Control ◽  
Glycogen Storage ◽  
Motor Nucleus ◽  
Rodent Models ◽  
Respiratory Dysfunction ◽  
Glycogen Accumulation ◽  
Search Terms ◽  
Respiratory Pathology

Pompe disease is a glycogen storage disease caused by a deficiency in acid α-glucosidase (GAA) – a hydrolase necessary for the degradation of lysosomal glycogen. This deficiency in GAA results in muscle and neuronal glycogen accumulation, which causes respiratory insufficiency. Pompe disease rodent models provide a means of assessing respiratory pathology and are important for pre-clinical studies of novel therapies that aim to treat respiratory dysfunction and improve quality of life. This review aims to compile and summarize existing manuscripts which characterize the respiratory phenotype of Pompe rodent models. Manuscripts included in this review were selected utilizing specific search terms and exclusion criteria. Analysis of these findings demonstrate that Pompe disease rodent models have respiratory physiological defects as well as pathologies in the diaphragm, tongue, phrenic and hypoglossal motor nucleus, phrenic and hypoglossal nerves, neuromuscular junctions, and airway smooth muscle and higher order respiratory control centers. Overall, the culmination of these pathologies contributes to severe respiratory dysfunction, underscoring the importance of characterizing the respiratory phenotype while developing effective therapies for patients.

scholarly journals Pompe disease, a storage cardiomyopathy

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Tiziana Felice
Keyword(s):  
Pompe Disease ◽  
Age Of Onset ◽  
Late Onset ◽  
Treatment Options ◽  
Premature Death ◽  
Glycogen Storage Disease Type ◽  
Lysosomal Storage ◽  
Respiratory Compromise ◽  
Enzyme Replacement ◽  
Geographical Regions

Pompe disease also known as glycogen storage disease type II, is a rare and progressive lysosomal storage disorder caused by the deficiency of the enzyme acid α-glucosidase. This results in the accumulation of glycogen in various tissues particularly involving the heart, skeletal muscle and liver. It is inherited in an autosomal recessive manner due to mutations in the GAA gene. There are several known pathogenic variants, some of which are particularly common in certain geographical regions. Pompe disease is a single disease exhibiting a heterogeneous clinical spectrum depending on the extent of enzyme deficiency, the age of onset, the progression of the disease and the degree of organ involvement. It may lead to muscle weakness, hypotonia, respiratory compromise and premature death. Pompe disease is classically divided into two forms, infantile and late-onset disease. The infantile form is further subdivided into classical and non-classical subtypes. Cardiac involvement is particularly seen in the infantile phenotype of the condition, presenting as severe cardiomyopathy associated with conduction abnormalities. Enzyme replacement therapy with recombinant human acid α-glucosidase is the approved treatment option for patients with this metabolic condition. Further research is currently being done to explore more treatment options. One must keep in mind other metabolic and mitochondrial conditions, which may give a similar cardiac and neurological clinical picture.

scholarly journals The Respiratory Phenotype of Pompe Disease Mouse Models

2020 ◽  
Vol 21 (6) ◽  
pp. 2256
Author(s):  
Anna F. Fusco ◽  
Angela L. McCall ◽  
Justin S. Dhindsa ◽  
Lucy Zheng ◽  
Aidan Bailey ◽  
...  
Keyword(s):  
Mouse Models ◽  
Pompe Disease ◽  
Neuromuscular Junctions ◽  
Respiratory Control ◽  
Glycogen Storage ◽  
Respiratory Dysfunction ◽  
Glycogen Accumulation ◽  
Search Terms ◽  
Respiratory Pathology

Pompe disease is a glycogen storage disease caused by a deficiency in acid α-glucosidase (GAA), a hydrolase necessary for the degradation of lysosomal glycogen. This deficiency in GAA results in muscle and neuronal glycogen accumulation, which causes respiratory insufficiency. Pompe disease mouse models provide a means of assessing respiratory pathology and are important for pre-clinical studies of novel therapies that aim to treat respiratory dysfunction and improve quality of life. This review aims to compile and summarize existing manuscripts that characterize the respiratory phenotype of Pompe mouse models. Manuscripts included in this review were selected utilizing specific search terms and exclusion criteria. Analysis of these findings demonstrate that Pompe disease mouse models have respiratory physiological defects as well as pathologies in the diaphragm, tongue, higher-order respiratory control centers, phrenic and hypoglossal motor nuclei, phrenic and hypoglossal nerves, neuromuscular junctions, and airway smooth muscle. Overall, the culmination of these pathologies contributes to severe respiratory dysfunction, underscoring the importance of characterizing the respiratory phenotype while developing effective therapies for patients.

Providing the conduit for treatment: The impact of vascular access and vein preservation in a 5-year-old child with prenatally diagnosed CRIM-negative Infantile Pompe disease

2021 ◽  
pp. 112972982199948
Author(s):  
Matthew Ostroff ◽  
Punita Gupta ◽  
Daniel Garcia
Keyword(s):  
Vascular Access ◽  
Pompe Disease ◽  
Disease Patient ◽  
Tolerance Induction ◽  
Glycogen Storage ◽  
Glycogen Accumulation ◽  
Enzyme Replacement ◽  
Infantile Pompe Disease ◽  
Glycogen Storage Disorder ◽  
The Impact

Pompe disease is an autosomal recessive glycogen storage disorder resulting in progressive glycogen accumulation expressed in infancy with cardiomyopathy and skeletal myopathy. Without treatment by enzyme replacement therapy (ERT), life expectancy is less than 2 years. The cross-reactive immunologic material (CRIM) positive or negative status is the basis for the response to ERT. CRIM-negative patients mount an immune response to ERT, making this the most dangerous presentation. The following case study describes the 5-year course of the first successful treatment of an in utero CRIM-negative Pompe disease patient with prophylactic immune tolerance induction (ITI) and administration of ERT given within the first 2 days of life followed by ultrasound guided vascular access that facilitated by bi-weekly infusions and extensive phlebotomy.

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