Therapeutic efficacy of 3,4-Diaminopyridine phosphate on neuromuscular junction in Pompe disease

Bragato, Cinzia; Blasevich, Flavia; Ингенито, Г.; Mantegazza, Renato; Maggi, Lorenzo

doi:10.1016/j.biopha.2021.111357

Cited by 5 publications

(3 citation statements)

References 37 publications

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“…The second day, embryos were treated with biotinylated or fluorescent secondary antibodies (Vector Laboratories, Newark, California, USA). Postsynaptic regions were labeled with Alexa Fluor 594 conjugated α‐bungarotoxin (Invitrogen corporation, Waltham, Massachusetts, USA) for 30 min as described in Bragato et al (2021).…”

Section: Methodsmentioning

confidence: 99%

Zebrafish dnm1a gene plays a role in the formation of axons and synapses in the nervous tissue

Bragato

Pistocchi

Bellipanni

et al. 2023

J of Neuroscience Research

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Classical dynamins (DNMs) are GTPase proteins engaged in endocytosis, a fundamental process for cargo internalization from the plasma membrane. In mammals, three DNM genes are present with different expression patterns. DNM1 is expressed at high levels in neurons, where it takes place in the recycling of synaptic vesicles; DNM2 is ubiquitously expressed, while DNM3 is found in the brain and in the testis. Due to the conservation of genes in comparison to mammals, we took advantage of a zebrafish model for functional characterization of dnm1a, ortholog of mammalian DNM1. Our data strongly demonstrated that dnm1a has a nervous tissue-specific expression pattern and plays a role in the formation of both axon and synapse. This is the first in vivo study that collects evidence about the effects of dnm1a loss of function in zebrafish, thus providing a new excellent model to be used in different scientific fields.

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Section: Methodsmentioning

confidence: 99%

Zebrafish dnm1a gene plays a role in the formation of axons and synapses in the nervous tissue

Bragato

Pistocchi

Bellipanni

et al. 2023

J of Neuroscience Research

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“…Symptomatic evidence guided Bragato and co-workers to identify the potential of amifampridine (3,4-diaminopyridine phosphate, or 3,4-DAP) for treating PD [ 63 ]. 3,4-DAP increases acetylcholine concentrations at the neuromuscular junction and is used as a symptomatic treatment for myasthenic syndromes, which are characterized by neuromuscular junction impairment, a feature of PD [ 64 ].…”

Section: Meet Serendipity Halfway: Targeted Drug Repositioningmentioning

confidence: 99%

Drug Repurposing and Lysosomal Storage Disorders: A Trick to Treat

Hay Mele,

Rossetti,

Cubellis

et al. 2024

Genes

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Rare diseases, or orphan diseases, are defined as diseases affecting a small number of people compared to the general population. Among these, we find lysosomal storage disorders (LSDs), a cluster of rare metabolic diseases characterized by enzyme mutations causing abnormal glycolipid storage. Drug repositioning involves repurposing existing approved drugs for new therapeutic applications, offering advantages in cost, time savings, and a lower risk of failure. We present a comprehensive analysis of existing drugs, their repurposing potential, and their clinical implications in the context of LSDs, highlighting the necessity of mutation-specific approaches. Our review systematically explores the landscape of drug repositioning as a means to enhance LSDs therapies. The findings advocate for the strategic repositioning of drugs, accentuating its role in expediting the discovery of effective treatments. We conclude that drug repurposing represents a viable pathway for accelerating therapeutic discovery for LSDs, emphasizing the need for the careful evaluation of drug efficacy and toxicity in disease-specific contexts.

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“…In addition to mouse models, a novel zebrafish model, in which GAA activity is significantly reduced but not totally absent, displays significant motor behavior and NMJ abnormalities ( Bragato et al, 2020 ). When this model was used as a drug screening platform, 3-bromopyruvic acid ( Bragato et al, 2020 ) and 3,4-diaminopyridine phosphate ( Cinzia et al, 2021 ) were found to increase AChR abundance, improve NMJ structure, and recover typical movement patterns. A baboon model of Pompe disease is currently used as a large animal preclinical model which has shown utility for therapeutic evaluation ( Rastall et al, 2016 ).…”

Section: Neuromuscular Diseasesmentioning

confidence: 99%

Neuromuscular Development and Disease: Learning From in vitro and in vivo Models

Fralish

Lotz

Chavez

et al. 2021

Front. Cell Dev. Biol.

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The neuromuscular junction (NMJ) is a specialized cholinergic synaptic interface between a motor neuron and a skeletal muscle fiber that translates presynaptic electrical impulses into motor function. NMJ formation and maintenance require tightly regulated signaling and cellular communication among motor neurons, myogenic cells, and Schwann cells. Neuromuscular diseases (NMDs) can result in loss of NMJ function and motor input leading to paralysis or even death. Although small animal models have been instrumental in advancing our understanding of the NMJ structure and function, the complexities of studying this multi-tissue system in vivo and poor clinical outcomes of candidate therapies developed in small animal models has driven the need for in vitro models of functional human NMJ to complement animal studies. In this review, we discuss prevailing models of NMDs and highlight the current progress and ongoing challenges in developing human iPSC-derived (hiPSC) 3D cell culture models of functional NMJs. We first review in vivo development of motor neurons, skeletal muscle, Schwann cells, and the NMJ alongside current methods for directing the differentiation of relevant cell types from hiPSCs. We further compare the efficacy of modeling NMDs in animals and human cell culture systems in the context of five NMDs: amyotrophic lateral sclerosis, myasthenia gravis, Duchenne muscular dystrophy, myotonic dystrophy, and Pompe disease. Finally, we discuss further work necessary for hiPSC-derived NMJ models to function as effective personalized NMD platforms.

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Therapeutic efficacy of 3,4-Diaminopyridine phosphate on neuromuscular junction in Pompe disease

Cited by 5 publications

References 37 publications

Zebrafish dnm1a gene plays a role in the formation of axons and synapses in the nervous tissue

Zebrafish dnm1a gene plays a role in the formation of axons and synapses in the nervous tissue

Drug Repurposing and Lysosomal Storage Disorders: A Trick to Treat

Neuromuscular Development and Disease: Learning From in vitro and in vivo Models

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