A Chaperone Enhances Blood α-Glucosidase Activity in Pompe Disease Patients Treated With Enzyme Replacement Therapy

Parenti, Giancarlo; Fecarotta, Simona; Marca, Giancarlo la; Rossi, Barbara; Ascione, Serena; Donati, Maria Alice; Morandi, Lucia; Ravaglia, Sabrina; Pichiecchio, Anna; Ombrone, Daniela; Sacchini, Michele; Pasanisi, Maria Barbara; Filippi, Paola De; Danesino, Cesare; Casa, Roberto Della; Romano, Alfonso; Mollica, Carmine; Rosa, Margherita; Agovino, Teresa; Nusco, Edoardo; Porto, Caterina; Andria, Generoso

doi:10.1038/mt.2014.138

Cited by 77 publications

(61 citation statements)

References 39 publications

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“…A similar trend was observed in the accumulation of the autophagic marker p62, which was lower in animals with higher muscle GAA activity after treatment. These results are in agreement with data showing that the combination of enzyme replacement therapy with chaperones, leading to a longer half-life of the stabilized rhGAA protein, results in greater therapeutic efficacy (54). …”

Section: Discussionsupporting

confidence: 92%

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

et al. 2017

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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.

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Section: Discussionsupporting

confidence: 92%

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

et al. 2017

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“…Efficient clearance of glycogen in ERT is hampered by both the potency of the hGAA to efficiently bind to the cell surface, as well as in trafficking to the lysosomal compartment. 34–37 Consistent with other related studies, 1,4,38,39 our data support the development of AAV9-hGAA to treat disorders associated with pathology of NMJ although highlight the importance of establishing markers of NMJ deterioration that could limit the functional benefit after gene therapy administration.…”

Section: Discussionsupporting

confidence: 90%

Correcting Neuromuscular Deficits With Gene Therapy in Pompe Disease

Todd

McElroy

Grange

et al. 2015

Annals of Neurology

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Objective We have recently reported on the pathology of the neuromuscular junction (NMJ) in Pompe disease, reflecting disruption of neuronal and muscle homeostasis as a result of glycogen accumulation. The aim of this study was to examine how the alteration of NMJ physiology contributes to Pompe disease pathology; we performed molecular, physiological, and histochemical analyses of NMJ-related measures of the tibialis anterior muscles of young-, mid-, and late-stage alpha-glucosidase (GAA)-deficient mice. Methods We performed intramuscular injection of an adeno-associated virus (AAV)9 vector expressing GAA (AAV9-hGAA) into the tibialis anterior muscle of Gaa–/– mice at early, mid, and severe pathological time points. We analyzed expression of NMJ-related genes, in situ muscle force production, and clearance of glycogen in conjunction with histological assessment of the NMJ. Results Our data demonstrate that AAV9-hGAA is able to replace GAA to the affected tissue and modify AChR mRNA expression, muscle force production, motor endplate area, and innervation status. Importantly, the degree of restoration for these outcomes is limited by severity of disease. Early restoration of GAA activity was most effective, whereas late correction of GAA expression was not effective in modifying parameters reflecting NMJ structure and function nor in force restoration despite resolution of glycogen storage in muscle. Interpretation Our data provide new mechanistic insight into the pathology of Pompe disease and suggest that early systemic correction to both neural and muscle tissues may be essential for successful correction of neuromuscular function in Pompe disease.

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“…The association between alpha-glucosidase and Gaucher disease is not evident; however, we found that this class of drug could be a chemical chaperone for misfolded alpha-glucosidase according to the recent report [56]. Moreover, because a recent repositioning study showed that anti-hypertensive and immunosuppressant class drugs might be efficacious in Gaucher disease [57–59] as well, we expect that the non-antibiotic drugs on our list may be effective in the disease (Table 3).…”

Section: Resultsmentioning

confidence: 67%

Drug repositioning for enzyme modulator based on human metabolite-likeness

et al. 2017

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BackgroundRecently, the metabolite-likeness of the drug space has emerged and has opened a new possibility for exploring human metabolite-like candidates in drug discovery. However, the applicability of metabolite-likeness in drug discovery has been largely unexplored. Moreover, there are no reports on its applications for the repositioning of drugs to possible enzyme modulators, although enzyme-drug relations could be directly inferred from the similarity relationships between enzyme’s metabolites and drugs.MethodsWe constructed a drug-metabolite structural similarity matrix, which contains 1,861 FDA-approved drugs and 1,110 human intermediary metabolites scored with the Tanimoto similarity. To verify the metabolite-likeness measure for drug repositioning, we analyzed 17 known antimetabolite drugs that resemble the innate metabolites of their eleven target enzymes as the gold standard positives. Highly scored drugs were selected as possible modulators of enzymes for their corresponding metabolites. Then, we assessed the performance of metabolite-likeness with a receiver operating characteristic analysis and compared it with other drug-target prediction methods. We set the similarity threshold for drug repositioning candidates of new enzyme modulators based on maximization of the Youden’s index. We also carried out literature surveys for supporting the drug repositioning results based on the metabolite-likeness.ResultsIn this paper, we applied metabolite-likeness to repurpose FDA-approved drugs to disease-associated enzyme modulators that resemble human innate metabolites. All antimetabolite drugs were mapped with their known 11 target enzymes with statistically significant similarity values to the corresponding metabolites. The comparison with other drug-target prediction methods showed the higher performance of metabolite-likeness for predicting enzyme modulators. After that, the drugs scored higher than similarity score of 0.654 were selected as possible modulators of enzymes for their corresponding metabolites. In addition, we showed that drug repositioning results of 10 enzymes were concordant with the literature evidence.ConclusionsThis study introduced a method to predict the repositioning of known drugs to possible modulators of disease associated enzymes using human metabolite-likeness. We demonstrated that this approach works correctly with known antimetabolite drugs and showed that the proposed method has better performance compared to other drug target prediction methods in terms of enzyme modulators prediction. This study as a proof-of-concept showed how to apply metabolite-likeness to drug repositioning as well as potential in further expansion as we acquire more disease associated metabolite-target protein relations.Electronic supplementary materialThe online version of this article (doi:10.1186/s12859-017-1637-5) contains supplementary material, which is available to authorized users.

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A Chaperone Enhances Blood α-Glucosidase Activity in Pompe Disease Patients Treated With Enzyme Replacement Therapy

Cited by 77 publications

References 39 publications

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

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

Correcting Neuromuscular Deficits With Gene Therapy in Pompe Disease

Drug repositioning for enzyme modulator based on human metabolite-likeness

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