Improved efficacy of a next-generation ERT in murine Pompe disease

Xu, Su; Yi, Long; Frascella, Michelle; Garcia, Anadina; Soska, Rebecca; Nair, Anju; Ponery, A. S.; Schilling, Adriane; Feng, Jessie; Tuske, Steve; Valle, Maria Cecilia Della; Martina, José A.; Ralston, Evelyn; Gotschall, Russell; Valenzano, Kenneth J.; Puertollano, Rosa; Do, Hung V.; Raben, Nina; Khanna, Richie

doi:10.1172/jci.insight.125358

Cited by 65 publications

(88 citation statements)

References 101 publications

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“…Importantly, recent data demonstrated that the reversal of autophagic pathology is feasible by using a more efficient next-generation drug for ERT. This new experimental drug, AT-GAA (Amicus Therapeutics) cleared muscle cells from lysosomal glycogen and reduced the number of myofibers with autophagic buildup in KO mice [71]. A similar reversal of autophagic accumulation in KO muscle has been recently achieved by gene therapy approaches [72,73].…”

Section: Lysosomes and Autophagy In Pompe Diseasementioning

confidence: 83%

Advancements in AAV-mediated Gene Therapy for Pompe Disease

Salabarria

Nair

Clément

et al. 2020

JND

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Pompe disease (glycogen storage disease type II) is caused by mutations in acid ␣-glucosidase (GAA) resulting in lysosomal pathology and impairment of the muscular and cardio-pulmonary systems. Enzyme replacement therapy (ERT), the only approved therapy for Pompe disease, improves muscle function by reducing glycogen accumulation but this approach entails several limitations including a short drug half-life and an antibody response that results in reduced efficacy. To address these limitations, new treatments such as gene therapy are under development to increase the intrinsic ability of the affected cells to produce GAA. Key components to gene therapy strategies include the choice of vector, promoter, and the route of administration. The efficacy of gene therapy depends on the ability of the vector to drive gene expression in the target tissue and also on the recipient's immune tolerance to the transgene protein. In this review, we discuss the preclinical and clinical studies that are paving the way for the development of a gene therapy strategy for patients with early and late onset Pompe disease as well as some of the challenges for advancing gene therapy.

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Section: Lysosomes and Autophagy In Pompe Diseasementioning

confidence: 83%

Advancements in AAV-mediated Gene Therapy for Pompe Disease

Salabarria

Nair

Clément

et al. 2020

JND

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“…In a large preclinical study in KO mice, AT-GAA was shown to significantly outperform alglucosidase alfa in all measured outcomes: GAA uptake and activity, muscle strength, reduction in lysosomal size and glycogen levels, and mitigation of autophagic defect [92]. Furthermore, long-term treatment of KO with AT-GAA completely reversed muscle lysosomal glycogen accumulation, eliminated autophagic buildup in >80% of muscle fibers, and to a large degree restored AMPK/mTORC1 signaling, muscle proteostasis, and metabolic abnormalities [66].…”

Section: Next-generation Ertmentioning

confidence: 99%

“…It is worth mentioning that metabolic pathways are highly conserved through evolution, and metabolic similarities between rodents and humans are very comparable despite the commonly observed differences in the phenotype of many mouse models of human diseases, including Pompe disease. In addition, a consistent increase in glycogen synthesis precursors in KO muscle-galactose 1-phosphate and UDP-glucose, the immediate glucose donor for glycogen synthesis-suggests inhibition of cytosolic glycogen synthesis [92]. Thus, progressive lysosomal glycogen accumulation in the diseased muscle sets off a cascade of events, such as altered autophagy and muscle proteostasis, oxidative stress, and dysregulation of major signaling and metabolic pathways (Figure 1).…”

Section: Beyond the Lysosome: Pathogenic Cascade And Muscle Regenerationmentioning

confidence: 99%

Pompe Disease: New Developments in an Old Lysosomal Storage Disorder

Meena

Raben

2020

Biomolecules

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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.

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“…This network comprises several ERresident chaperones and degradation elements as well as stressresponsive signaling pathways that detect the misfolding and/or aggregation of proteins in specific subcellular compartments using stress sensors, which respond by generating an active transcription factor (Roth and Balch, 2011;Klionsky et al, 2016;Kelly, 2020). ERT-IV (rhGAA-ATB200)/PC (AT2221)/ODD None (Xu et al, 2019) Metachromatic Leukodystrophy…”

Section: Pharmacological Chaperones (Pc)mentioning

confidence: 99%

CNS-Targeting Therapies for Lysosomal Storage Diseases: Current Advances and Challenges

Edelmann

Maegawa

2020

Front. Mol. Biosci.

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During the past decades, several therapeutic approaches have been developed and made rapidly available for many patients afflicted with lysosomal storage disorders (LSDs), inborn organelle disorders with broad clinical manifestations secondary to the progressive accumulation of undegraded macromolecules within lysosomes. These conditions are individually rare, but, collectively, their incidence ranges from 1 in 2,315 to 7,700 live-births. Most LSDs are manifested by neurological symptoms or signs, including developmental delay, seizures, acroparesthesia, motor weakness, and extrapyramidal signs. The chronic and later-onset clinical forms are at one end of the continuum spectrum and are characterized by a subtle and slow progression of neurological symptoms. Due to its inherent physiological properties, unfortunately, the blood-brain barrier (BBB) constitutes a significant obstacle for current and upcoming therapies to achieve the central nervous system (CNS) and treat neurological problems so prevalent in these conditions. To circumvent this limitation, several strategies have been developed to make the therapeutic agent achieve the CNS. This narrative will provide an overview of current therapeutic strategies under development to permeate the BBB, and address and unmet need for treatment of the progressive neurological manifestations, which are so prevalent in these inherited lysosomal disorders.

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Improved efficacy of a next-generation ERT in murine Pompe disease

Cited by 65 publications

References 101 publications

Advancements in AAV-mediated Gene Therapy for Pompe Disease

Advancements in AAV-mediated Gene Therapy for Pompe Disease

Pompe Disease: New Developments in an Old Lysosomal Storage Disorder

CNS-Targeting Therapies for Lysosomal Storage Diseases: Current Advances and Challenges

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