The most common type of Charcot-Marie-Tooth disease (CMT1A) is associated with a duplication of PMP22, leading to dysmyelination, axonal loss, progressive weakness and wasting of the muscles, chronic pain, and muscle cramps.1 Although the overexpression of PMP22 is a hallmark feature of the disease, the molecular mechanisms that lead to CMT1A phenotype remain unknown.
Currently, no approved treatment for CMT1A patients is available. Thus, in order to understand the mechanisms underlying CMT1A and develop a therapeutic strategy to treat the disease, a rat model overexpressing the Pmp22 mouse gene was generated.2 The pathology in CMT1A rats mimicked closely the pathophysiological features of the human disease, such as loss of muscle strength and nerve sensitivity.
The novel polytherapeutic drug combination PXT3003 (a low dose of baclofen, naltrexone, and sorbitol) was previously administered to CMT1A rats and demonstrated a positive efficacy to slow down disease progression after 3 months of treatment. Moreover, in a Schwannoma cell model PXT3003 decreased Pmp22 expression. Furthermore, the treatment improved myelination in a dorsal root ganglion co-culture model derived from CMT1A transgenic rats.3 Interestingly, it has also been demonstrated that an early short-term treatment of 2 weeks with PXT3003, starting at postnatal Day 6 in CMT1A rats, was enough to alleviate motor and molecular deficits 3 months later. This data suggested that PXT3003 is a potential promising therapy for children and young adolescent CMT1A patients.4 Finally, a clinical Phase III study recently revealed positive efficacy in CMT1A adult patients.5
Here, the authors performed a long-term treatment study in adult CMT1A rats with PXT3003 to test the superior effect of PXT3003 compared to its three binary combinations of baclofen/naltrexone, baclofen/sorbitol, and naltrexone/sorbitol, and to demonstrate the contribution of each compound in the global efficacy of PXT3003 on CMT1A symptoms. CMT1A and wildtype rats were included as placebo controls. The treatment was performed in adult rats starting at postnatal Week 6, after the manifestation of symptoms commonly observed in CMT1A rats, and was continued until 18 weeks of age. Behavioural analyses were performed at the age of 6, 10, 14, and 18 weeks (grip strength, bar test, and inclined plane test). Furthermore, electrophysiological measurements and hot plate test were carried out at the end of the study. Post-mortem histological analyses were also performed to study the effect of PXT3003 on neuromuscular junctions and muscle function alterations.
PXT3003 treatment for 3 months starting in clinically affected adult rats improved the motor and sensory functions of CMT1A animals. The data suggest a synergistic effect of the three drug components contained in PXT3003: no significant effect on motor endpoints was actually observed with any of the binary combinations of baclofen/naltrexone, baclofen/sorbitol, or naltrexone/sorbitol, while in contrast, PXT3003 was significantly efficacious and proved its superior efficacy to the binary combinations on the behavioral level in CMT1A rats. Electrophysiological recordings revealed an improvement in distal motor latencies after PXT3003 treatment. This data also demonstrated that PXT3003 treatment restored functional neuromuscular innervation, which may be responsible for the observed correction in muscle fiber composition and subsequent increased muscle strength.
In conclusion, baclofen, naltrexone, and sorbitol all contribute to the effect of PXT3003 in CMT1A disease. The authors hypothesise that PXT3003 improves the function of neuromuscular junctions and consecutive muscle innervation, which may contribute to the improved motor function observed in CMT1A rats.