Treating PMP22 gene duplication-related Charcot-Marie-Tooth disease: the past, the present and the future

Boutary, Suzan; Echaniz‐Laguna, Andoni; Adams, David H.; Loisel‐Duwattez, Julien; Schumacher, Michaël; Massaad, Charbel; Massaad-Massade, Liliane

doi:10.1016/j.trsl.2020.07.006

Cited by 36 publications

(35 citation statements)

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“…Dysmyelination was detected in young patients with CMT1A without affecting the NCV whereas; demyelination was detected in adults CMT1A patients 34 . Therefore, we believe that these models are representative of CMT1A neuropathy and are good candidates for gene therapy studies 7 . Consistently, a 1.8-fold increase in Pmp22 protein levels was observed in the JP18 group and a threefold increase in the JP18/JY13 group when compared to wild-type B6 (WT) mice ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…To date, there has been no effective treatment for CMT1A 7 . Existing therapies aim to reduce its progression through rehabilitation and surgical corrections.…”

mentioning

confidence: 99%

“…Most of the therapeutic interventions include modulators of adenylate cyclase activity, such as ascorbic acid 8 and combination therapy PXT 3003 9 , neurotrophin-3 10 , an antagonist of the progesterone receptor (Onapristone) 11 and pain-modulating drugs (ADX71441 12 and FLX-787 13 ). However, these molecules did not reach clinics due to their inefficiency or toxicity in clinical trials 7 . More recently, genetic therapy was introduced by Zhao et al by using antisense oligonucleotides (ASO) in CMT1A animal models and showed promising results 14 .…”

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confidence: 99%

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Squalenoyl siRNA PMP22 nanoparticles are effective in treating mouse models of Charcot-Marie-Tooth disease type 1 A

et al. 2021

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Charcot-Marie-Tooth disease type 1 A (CMT1A) lacks an effective treatment. We provide a therapy for CMT1A, based on siRNA conjugated to squalene nanoparticles (siRNA PMP22-SQ NPs). Their administration resulted in normalization of Pmp22 protein levels, restored locomotor activity and electrophysiological parameters in two transgenic CMT1A mouse models with different severity of the disease. Pathological studies demonstrated the regeneration of myelinated axons and myelin compaction, one major step in restoring function of myelin sheaths. The normalization of sciatic nerve Krox20, Sox10 and neurofilament levels reflected the regeneration of both myelin and axons. Importantly, the positive effects of siRNA PMP22-SQ NPs lasted for three weeks, and their renewed administration resulted in full functional recovery. Beyond CMT1A, our findings can be considered as a potent therapeutic strategy for inherited peripheral neuropathies. They provide the proof of concept for a new precision medicine based on the normalization of disease gene expression by siRNA.

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Section: Resultsmentioning

confidence: 99%

“…To date, there has been no effective treatment for CMT1A 7 . Existing therapies aim to reduce its progression through rehabilitation and surgical corrections.…”

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confidence: 99%

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Squalenoyl siRNA PMP22 nanoparticles are effective in treating mouse models of Charcot-Marie-Tooth disease type 1 A

et al. 2021

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“…It is known that the development of neuropathy is accompanied by motor and sensory disorders, which manifest themselves in the form of progressive muscle weakness, incoordination and decreased tactile sensitivity of the distal regions of limbs. Morphologically, CMT1A manifests itself in the form of loss of the myelin sheath of nerve fibers, the formation of areas of abnormal myelination (onion bulbs), and axonal dystrophy [1]. With the progression of this disease there is a disorder of axonal transport and trophic functions of Schwann cells, which leads to atrophy of the distal axons [1,4].…”

Section: X-axis Is the Time (In Weeks) After Adscs Transplantationmentioning

confidence: 99%

“…The cause of CMT1A is the duplication of a fragment of chromosome 17p.11.2 that leads to the appearance of the third allele of the gene of peripheral myelin protein 22 kDa (PMP22), which causes its overexpression [2]. PMP22 protein is an integral membrane protein of the tetraspan family, which accounts for 2-5 % of the total number of proteins of the compact myelin layer of the peripheral nervous system [1,3]. The specific functions of PMP22 have not been established yet, but it is known that PMP22 is involved in maintaining the stability of lipid rafts on Schwann cell membranes and the processes of myelin membrane formation during axonal myelination [3,4].…”

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The effects of adipose-derived multipotent mesenchymal stromal cells transplantation on motor activity and function of the sciatic nerve in mice with peripheral neuropathy

Rubtsov¹,

Govbach²,

Ustymenko³

et al. 2020

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The Charcot–Marie–Tooth disease type 1A (SHMT1A) is one of the most common hereditary motor-sensory peripheral neuropathies, which is caused by demyelination of motor and sensory nerve fibers and leads to nerve dysfunction. There are currently no effective treatments for hereditary neuropathies, but recent studies indicate a number of potentially effective therapeutic agents, including multipotent mesenchymal stromal cells (MMSCs). The aim of the study was to evaluate the effect of adipose-derived MMSCc transplantation on motor activity and sciatic nerve function of transgenic mice with peripheral neuropathy. Materials and methods. The transgenic B6.Cg-Tg(PMP22)C3Fbas/J mice with peripheral neuropathy were injected intramuscularly with MMSCs, which were isolated from the adipose tissue of FVB-Cg-Tg(GFPU) mice transgenic by GFP. Motor activity of experimental animals was investigated in dynamics after 2, 4, 6, 8 and 10 weeks using the behavioral balance beam test. The functions of the sciatic nerve were analyzed according to the footprint test by calculating the sciatic functional index (SFI). Results. For 2-10 weeks in animals with neuropathy, disease progression was observed, which was expressed in an increasing increase in the number of slidings of the hind limbs from the beam and the time required to walking the distance. SFI in animals of this group decreased and at the 10th week was -47.0 ± 2 units. In contrast, from the 2nd week of the experiment, mice with neuropathy after MMSCs transplantation performed 20 % fewer slidings and spent 11 % less time in the balance beam test compared to animals without cell transplantation. In the same period, an increase of SFI up to -30.2 ± 2 versus -34.6 ± 0.9 units was observed, respectively. At the 10th week after the injection of MMSC, the SFI value was -10.1 ± 2.3 units and correlated with a decrease in the number of slidings and the time spent on the balance beam test. Conclusions. MMSCs transplantation improves the sciatic functional index and fine motor skills in mice with peripheral neuropathy. MMSCs have the potential to be an effective therapeutic agent in the treatment of peripheral neuropathy at Charcot-Marie-Tooth disease.

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Lower limb muscle MRI fat fraction is a responsive outcome measure in CMT X1, 1B and 2A

Doherty,

Morrow,

Zuccarino

et al. 2024

Ann Clin Transl Neurol

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ObjectiveWith potential therapies for many forms of Charcot‐Marie‐Tooth disease (CMT), responsive outcome measures are urgently needed for clinical trials. Quantitative lower limb MRI demonstrated progressive calf intramuscular fat accumulation in the commonest form, CMT1A with large responsiveness. In this study, we evaluated the responsiveness and validity in the three other common forms, due to variants in GJB1 (CMTX1), MPZ (CMT1B) and MFN2 (CMT2A).Methods22 CMTX1, 21 CMT1B and 21 CMT2A patients and matched controls were assessed at a 1‐year interval. Intramuscular fat fraction (FF) was evaluated using three‐point Dixon MRI at thigh and calf level along with clinical measures including CMT examination score, clinical strength assessment, CMT‐HI and plasma neurofilament light chain.ResultsAll patient groups had elevated muscle fat fraction at thigh and calf levels, with highest thigh FF and atrophy in CMT2A. There was moderate correlation between calf muscle FF and clinical measures (CMTESv2 rho = 0.405; p = 0.001, ankle MRC strength rho = −0.481; p < 0.001). Significant annualised progression in calf muscle FF was seen in all patient groups (CMTX1 2.0 ± 2.0%, p < 0.001, CMT1B 1.6 ± 2.1% p = 0.004 and CMT2A 1.6 ± 2.1% p = 0.002). Greatest increase was seen in patients with 10–70% FF at baseline (calf 2.7 ± 2.3%, p < 0.0001 and thigh 1.7 ± 2.1%, p = 0.01).InterpretationOur results confirm that calf muscle FF is highly responsive over 12 months in three additional common forms of CMT which together with CMT1A account for 90% of genetically confirmed cases. Calf muscle MRI FF should be a valuable outcome measure in upcoming CMT clinical trials.

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Treating PMP22 gene duplication-related Charcot-Marie-Tooth disease: the past, the present and the future

Cited by 36 publications

References 123 publications

Squalenoyl siRNA PMP22 nanoparticles are effective in treating mouse models of Charcot-Marie-Tooth disease type 1 A

Squalenoyl siRNA PMP22 nanoparticles are effective in treating mouse models of Charcot-Marie-Tooth disease type 1 A

The effects of adipose-derived multipotent mesenchymal stromal cells transplantation on motor activity and function of the sciatic nerve in mice with peripheral neuropathy

Lower limb muscle MRI fat fraction is a responsive outcome measure in CMT X1, 1B and 2A

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