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

Abstract

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.

Nerve damage induced skeletal muscle atrophy is associated with increased accumulation of intramuscular glucose and polyol pathway intermediates

“…Indeed, in another neurological disease associated with motor neuron damage, muscle atrophy and a metabolic phenotype, Charcot-Marie-Tooth disease (CMT), the polyol pathway intermediate sorbitol is currently tested in a phase III clinical trial as part of a combination of treatments for CMT type 1 A (NCT03023540). Previous data in animals and a phase II trial suggest a moderate effect on myelination and muscular performance, particularly when sorbitol is used in conjunction with the other two treatment components (baclofen, naltrexone) [27][28][29] . While it seems unlikely that sorbitol alone would exhibit a substantial effect on disease progression and muscle loss for any neuromuscular disease, it does indicate that there could be a physiological and potentially even mildly beneficial role for sorbitol as a substrate in those conditions.…”

Synergistic PXT3003 therapy uncouples neuromuscular function from dysmyelination in male Charcot–Marie–Tooth disease type 1A (CMT1A) rats

“…In CMT1A patients, PXT3003 was effective on clinical endpoints in a phase 2 study (Attarian et al, 2014(Attarian et al, , 2016, and effects were also confirmed in a first analysis of a phase 3 international study (Clinical Trials Register/Results, 2019). However, the contribution of the single components to the overall efficacy of PXT3003 remained elusive, and recent preclinical data suggested beneficial effects beyond improving the known nerve pathology (Prukop et al, 2019). To address these questions, we compared PXT3003 and its components in CMT1A rats and extended our analyses to the neuromuscular unit apart from the motoneuron, that is, the peripheral nerve, the neuromuscular junction (NMJ), and the muscle.…”

“…The number of animals used in the studies was defined by a-priori power analysis taking own experience with the CMT1A rat model into consideration aiming at the demonstration of significant grip strength effects (Fledrich et al, 2012(Fledrich et al, , 2014Meyer zu Horste et al, 2007;Prukop et al, 2019;Sereda, Meyer zu Hörste, Suter, Uzma, & Nave, 2003;Sociali et al, 2016).…”

“…These data fit well to our findings in the muscle although its interpretation remains limited due to small given sample sizes. Angular muscle fibers are considered as an indirect parameter of neurogenic atrophy (Ericson, Ansved, & Borg, 1998) in CMT1A which appears uncoupled from the degree of peripheral nerve myelination and which may constitute a new pharmacological target for PXT3003 therapy in adult animals (Prukop et al, 2019).…”

Aktuelles zur Charcot-Marie-Tooth-Erkrankung

“…Ziel der Substanzkombination ist es, die Überexpression von PMP22 synergistisch zu senken. In PMP22 transgenen Ratten konnte eine frühe Behandlung mit PXT3003 die Symptome partiell verhindern [72]. Andere Behandlungen, die auf die PMP22-Reduktion auf transkriptioneller Ebene abzielen, erwiesen sich in vorklinischen Studien als wirksam, zum Beispiel Progesteronantagonisten [73].…”