Antisense oligonucleotides offer hope to patients with Charcot-Marie-Tooth disease type 1A

Shy, Michael E.

doi:10.1172/jci98617

Cited by 10 publications

(4 citation statements)

References 15 publications

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“…In contrast to progesterone antagonists [32,34], the growth factor neuregulin [27] or, more recently, Pmp22 -targeting antisense oligonucleotides [35,36], a preclinical early treatment trial in young CMT1A rats with PXT3003 is more easily translatable to young adults or even children with CMT1A due to its good safety profile. No adverse effects were observed in the wildtype or CMT1A rats treated with PXT3003 with regard to the weight, phenotype, electrophysiological parameters, histological abnormalities and molecular biology.…”

Section: Discussionmentioning

confidence: 99%

Early short-term PXT3003 combinational therapy delays disease onset in a transgenic rat model of Charcot-Marie-Tooth disease 1A (CMT1A)

et al. 2019

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The most common type of Charcot-Marie-Tooth disease is caused by a duplication of PMP22 leading to dysmyelination, axonal loss and progressive muscle weakness (CMT1A). Currently, no approved therapy is available for CMT1A patients. A novel polytherapeutic proof-of-principle approach using PXT3003, a low-dose combination of baclofen, naltrexone and sorbitol, slowed disease progression after long-term dosing in adult Pmp22 transgenic rats, a known animal model of CMT1A. Here, we report an early postnatal, short-term treatment with PXT3003 in CMT1A rats that delays disease onset into adulthood. CMT1A rats were treated from postnatal day 6 to 18 with PXT3003. Behavioural, electrophysiological, histological and molecular analyses were performed until 12 weeks of age. Daily oral treatment for approximately 2 weeks ameliorated motor deficits of CMT1A rats reaching wildtype levels. Histologically, PXT3003 corrected the disturbed axon calibre distribution with a shift towards large motor axons. Despite dramatic clinical amelioration, only distal motor latencies were improved and correlated with phenotype performance. On the molecular level, PXT3003 reduced Pmp22 mRNA overexpression and improved the misbalanced downstream PI3K-AKT / MEK-ERK signalling pathway. The improved differentiation status of Schwann cells may have enabled better long-term axonal support function. We conclude that short-term treatment with PXT3003 during early development may partially prevent the clinical and molecular manifestations of CMT1A. Since PXT3003 has a strong safety profile and is currently undergoing a phase III trial in CMT1A patients, our results suggest that PXT3003 therapy may be a bona fide translatable therapy option for children and young adolescent patients suffering from CMT1A.

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Section: Discussionmentioning

confidence: 99%

Early short-term PXT3003 combinational therapy delays disease onset in a transgenic rat model of Charcot-Marie-Tooth disease 1A (CMT1A)

et al. 2019

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“…Initiation of ASO treatment restored impressively myelination, motor nerve conduction velocity and compound muscle action potentials almost to levels seen in wild type animals (36). These data demonstrate that strategies to reduce PMP22 have potential as effective therapeutic approaches for CMT1A (37).…”

Section: Peripheral Nerve Diseases/charcot-marie-tooth Disorders (Cmts)mentioning

confidence: 57%

New Therapeutics Options for Pediatric Neuromuscular Disorders

Flotats‐Bastardas

Hahn

2020

Front. Pediatr.

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Neuromuscular disorders (NMDs) of Childhood onset are a genetically heterogeneous group of diseases affecting the anterior horn cell, the peripheral nerve, the neuromuscular junction, or the muscle. For many decades, treatment of NMDs has been exclusively symptomatic. But this has changed fundamentally in recent years due to the development of new drugs attempting either to ameliorate secondary pathophysiologic consequences or to modify the underlying genetic defect itself. While the effects on the course of disease are still modest in some NMDs (e.g., Duchenne muscular dystrophy), new therapies have substantially prolonged life expectancy and improved motor function in others (e.g., spinal muscular atrophy and infantile onset Pompe disease). This review summarizes recently approved medicaments and provides an outlook for new therapies that are on the horizon in this field.

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“…At the same time, important challenges remain. Specifically, the timing of ASO treatment, as well as mode of administration and dose, will all require further investigation [155]. Furthermore, concerns about offtarget effects, and the known side effects of ASOs including thrombocytopenia, could outweigh the benefit of treatment for a slowly progressive neuropathy such as CMT1A [156].…”

Section: Emerging Genetic Therapies In Cmt1amentioning

confidence: 99%

Mechanisms and Treatments in Demyelinating CMT

Fridman

Saporta

2021

Neurotherapeutics

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Demyelinating forms of Charcot-Marie-Tooth disease (CMT) are genetically and phenotypically heterogeneous and result from highly diverse biological mechanisms including gain of function (including dominant negative effects) and loss of function. While no definitive treatment is currently available, rapid advances in defining the pathomechanisms of demyelinating CMT have led to promising pre-clinical studies, as well as emerging clinical trials. Especially promising are the recently completed pre-clinical genetic therapy studies in PMP-22, GJB1, and SH3TC2-associated neuropathies, particularly given the success of similar approaches in humans with spinal muscular atrophy and transthyretin familial polyneuropathy. This article focuses on neuropathies related to mutations in PMP-22, MPZ, and GJB1, which together comprise the most common forms of demyelinating CMT, as well as on select rarer forms for which promising treatment targets have been identified. Clinical characteristics and pathomechanisms are reviewed in detail, with emphasis on therapeutically targetable biological pathways. Also discussed are the challenges facing the CMT research community in its efforts to advance the rapidly evolving biological insights to effective clinical trials. These considerations include the limitations of currently available animal models, the need for personalized medicine approaches/allele-specific interventions for select forms of demyelinating CMT, and the increasing demand for optimal clinical outcome assessments and objective biomarkers.

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Antisense oligonucleotides offer hope to patients with Charcot-Marie-Tooth disease type 1A

Cited by 10 publications

References 15 publications

Early short-term PXT3003 combinational therapy delays disease onset in a transgenic rat model of Charcot-Marie-Tooth disease 1A (CMT1A)

Early short-term PXT3003 combinational therapy delays disease onset in a transgenic rat model of Charcot-Marie-Tooth disease 1A (CMT1A)

New Therapeutics Options for Pediatric Neuromuscular Disorders

Mechanisms and Treatments in Demyelinating CMT

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