Cmt 54 pdf

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Just before I checked the board, I was soldering the 2 broken off legs and the body and center pin to a piece of perf. The plan was to get everything lined back up PITA, taking forever , then I would use hot melt glue to physically lock everything in place. Post-onset treatment in 6-month-old Gjb1 -null mice reproduced the results of early treatment [ 23 ] providing further support for this approach in CMT1X patients with mostly advanced neuropathy by early adulthood.

Finally, since the majority of CMT1X patients do not lack Cx32 production completely, but rather produce mutant Cx32 that is abnormally retained intracellularly, further studies were undertaken to treat transgenic mice producing representative Cx32 mutant proteins, some of which have shown direct interaction with co-produced WT Cx32 [ , ].

Lentiviral gene therapy showed that virally delivered GJB1 gene encoding WT Cx32 could overcome the effects of the ER-retained mutant Cx32 protein with T55I substitution, but therapeutic effects were greatly diminished in the presence of Golgi-retained Cx32 mutants with R75W and ND amino acid residue substitutions [ 22 ].

Since treatment with lentiviral vectors could not overcome the effects of some Cx32 mutants and given the limitations of its use due to risk of insertional mutagenesis with systemic in vivo delivery above , efforts have now focused on developing gene therapy for CMT1X using AAV vectors. Treatment study in the two groups showed both functional and morphological improvements Figure 1. Two clinically relevant blood biomarkers, elevated neurofilament light NFL and the neural cell adhesion molecule-1 NCAM-1 , showed response to treatment as well [ 34 ].

It remains to be seen whether the AAV-based approach can be adequately scaled-up in terms of biodistribution to be feasible for clinical application, and whether higher levels of AAV-driven production of WT Cx32 can overcome the interfering effects of certain Golgi-retained Cx32 mutants. Toluidine blue stained femoral motor nerve semithin sections from month old Gjb1 -null mice treated post-onset at 6 months of age with intrathecal delivered mock vector AAV9- Mpz.

Egfp , left or with AAV9- Mpz. GJB1 vector right in Schwann cells, shows improvement of myelination defects including the remyelinated r and demyelinated asterisk fibers. Modified from [ 34 ]. NT-3 based gene therapy of CMT1X, resulted in significant improvement of the demyelinating neuropathy in the pre-onset Gjb1 -null model as indicated by electrophysiological and morphological improvements.

Despite this beneficial effect, this approach does not directly solve the cause of the disease and its translation potential remains to be demonstrated. A potential alternative or complementary therapeutic target for CMT1X is the modification of inflammatory processes that are prominent at least in the mouse model of the disease, in which the presence of foamy macrophages is a characteristic feature of nerve pathology [ ].

Several studies have focused on the treatment of CMT1X through amelioration of inflammation. Further studies showed that a macrophage-directed CSF-1 mediates the pathology in Gjb1 -null mice, whereas inhibiting the interaction of CSF-1 with its receptor improved nerve pathology [ , , ].

Especially secreted proteoglycan CSF-1 spCSF-1 is related to the macrophage activation and macrophage-related neural damage, while cell surface glycoprotein CSF-1 csCSF-1 inhibits macrophage activation and attenuates neuropathy [ ]. Further studies will be needed to develop clinically useful therapeutics with adequate biodistribution and access to the PNS in order to address this facet of CMT1X pathology.

These studies provide proof of principle for translatable therapeutics to treat CMT4B, and future clinical trials are awaited. The localization of SH3TC2 protein in early and late endosomes of the endocytic pathway, in clathrin-coated vesicles in trans-Golgi network, and at the plasma membrane is disrupted when CMT4C causing mutated alleles of SH3TC2 are expressed in vitro.

A lentiviral system was developed to drive the expression of the human SH3TC2 under the control of the rat Mpz promoter. LV- Mpz. This resulted in behavioral and electrophysiological improvements in treated mice. Moreover, morphological analysis revealed significant reduction in the ratio of the inner to the outer diameter of the myelin sheath g-ratio and increase in myelin thickness after treatment along with improved nodal molecular architecture.

A more clinically translatable gene therapy approach for CMT4C remains to be developed in order to facilitate treatment for patients. Gene therapy using AAV9 delivery of a codon-optimized human FIG4 gene was effective in improving survival rate, motor performance, neurophysiological parameters and morphological abnormalities in the pale tremor mouse plt model of CMT4J [ ].

While intracerebroventricular ICV delivery of AAV9- FIG4 vector at postnatal day PND 1 or 4 extended the life span of the plt mice from a few weeks to at least a year, delayed treatment at PND 7 or 11 with intrathecal injection resulted in incomplete phenotype rescue, although it still provided benefit.

Mutations in the MFN2 gene can be either hereditary mostly autosomal dominant or may occur de novo [ ] and have been shown to result in disruption of normal mitochondrial fusion. This leads to abnormal mitochondrial aggregation and function, along with dysfunctional subcellular mitochondrial trafficking [ , ].

Thus, peripheral nerves consisting of longer axon projections are the most affected in CMT2A patients, possibly due to higher energy demands compared to other cell types. Axonal degeneration is the hallmark of many neurological disorders, including CMT2A, and is considered to be a genetically encoded program of subcellular self-destruction. Intramolecular rearrangement of the molecule leads to dimerization of the TIR motifs and eventually to degeneration of injured axons [ ], while SARM1 activation leads to axonal degeneration even in the absence of injury [ ].

Loss of mitochondrial membrane potential leads to reduction of the axon survival factor NMNAT2 which will then activate SARM1 leading to axonal degeneration [ , ]. Since no small molecules are available to inhibit SARM1 action in vivo, a gene therapy approach has been developed using dominant negative SARM1 mutants synergistically packaged into an AAV8 capsid [ 47 ].

Although there are currently no therapeutics that can directly reverse mitochondrial defects in CMT2A, MFN2 activators have been identified offering a potential therapeutic approach.

Novel small-molecule mitofusin agonists were shown to allosterically activate MFN2 reversing the morphological alterations of neuronal mitochondrial defects as well as their impaired mobility caused by two MFN2 gene mutations in vitro. Moreover, a mitofusin agonist normalized the axonal mitochondrial trafficking in ex vivo sciatic nerves of MFN2 mutant mice [ ].

Because these prototype compounds had poor pharmacokinetic properties in vivo, a series of 6-phenylhexanamide derivative mitofusin activators were designed and tested in vivo.

This led to the identification of compound 13B as the most promising candidate, as it showed adequate oral bioavailability and increased the number and the motility of mitochondria in the sciatic nerve axons [ ].

Indeed, overexpressing MFN1 in the nervous system of MFN2 R94Q mutant mice resulted in improved body weight, better behavioral performance and visual acuity, longer survival, as well as reduced mitochondrial aggregation and axon degeneration.

Distal hereditary motor neuropathy dHMN is a recently characterized autosomal recessive disease caused by sorbitol dehydrogenase SORD gene mutations [ ]. SORD mutations result in decreased levels and lost function of the SORD enzyme, leading to neuronal sorbitol accumulation, a mechanism previously shown to induce neuropathy in a diabetic mouse model [ ]. The polyol pathway in which glucose is converted to sorbitol, has received attention for the treatment of diabetic polyneuropathy and eventually dHMN-SORD [ ].

Aldose reductase is a key enzyme in this pathway and its inhibitors have been extensively used in clinical trials. Epalrestat is an aldose reductase inhibitor that was well absorbed into the neural tissue and prevented significantly the decrease of the motor nerve conduction velocity in a diabetic neuropathy model [ ].

These beneficial effects in diabetic neuropathy were reproduced with another aldose reductase inhibitor, ranirestat [ ]. When epalrestat and ranirestat were used on cultured fibroblasts from patients with SORD mutations, elevated sorbitol levels were significantly ameliorated [ ], offering a promising approach to treat patients suffering from dHMN-SORD. Toxic gain-of-function effects of GARS mutations has been demonstrated as overexpression of WT GARS did not improve the pathological phenotype of two transgenic mouse models of the disease [ ].

Thus, suppression of the mutant GARS allele should be of therapeutic benefit. However, therapeutic benefit could be achieved only with pre-onset but not with post-onset treatment, and the models used did not express GARS mutations causing single amino acid substitutions as found in CMT2D patients, but 5 or 12 base pair changes, making them an easier target for allele-specific RNAi sequences. NFL is a major constituent of intermediate filaments and plays a pivotal role in the assembly and maintenance of axonal cytoskeleton.

Giant axons are a histological hallmark frequently seen in nerves of patients with CMT2E. Heat shock proteins HSPs are involved in the formation of the neurofilament network and in protecting cells from misfolded mutant proteins.

Rounding of mitochondria and reduction in axonal diameter occurs before disruption of the neurofilament network, indicating that mitochondrial dysfunction contributes to the pathogenesis of CMT2E. Comparison of neuroprotective effects in a primary motor neuron culture model of CMT2E showed that HSPA1 and HSPB1 overexpression prevented neurofilament abnormalities as well as mitochondrial and axonal alterations but their efficacy depended on the specific NEFL mutated allele expressed [ ].

These findings support the potential use of chaperone-based therapies for the treatment of CMT2E. In vivo validation remains to be shown for these therapeutics. HSPB1 is a multifunctional protein with roles in protein aggregation, apoptosis, cytoskeletal maintenance, and gene transcription. Furthermore, blocking HDAC6 activity, which is implicated in impaired mitochondrial transport and axon growth inhibition [ ], reversed axonal loss and muscle denervation in a mouse model of CMT2F [ ].

This approach also benefited CMT2D disease models [ ]. This treatment showed high efficacy with amelioration of motor dysfunction and muscle degeneration. Moreover, in another treatment trial using nmd mice, ICV injection resulted in significantly improved muscle pathology and prevented motor neuron loss.

However, optimal dosing remains a crucial parameter to be addressed as overexpression of IGHMBP2 may also have a detrimental effect [ ]. Overall, several promising therapeutics are on the horizon for axonal CMT types, including some that target specifically the disease pathogenesis, and others that target pathways of mitochondrial dysfunction and axonal degeneration, that may be applicable to most if not all CMT types.

While there is a multitude of emerging treatments currently studied for CMT neuropathies, they remain mostly at the pre-clinical level and their clinical translation creates major challenges ahead.

As outlined above, clinical trials have mostly been conducted for the treatment of the most common type, CMT1A, often with discouraging results. One of the major hurdles was the unavailability of sensitive outcome measures that would allow the detection of treatment response in a slowly progressive chronic disease such as CMT1A, which also shows marked phenotypic variability.

These issues are relevant to other CMT neuropathies as well, but in addition, due to the fact that they are much more rare compared to CMT1A, or even ultra-rare, additional challenges of special clinical trial design will have to be overcome in order to achieve successful clinical application of promising experimental therapeutics.

Below we discuss the need for more accurate outcome measures, novel biomarkers, and for optimal clinical trial design, as they apply to most CMT neuropathies. Efforts over the last 10 years have focused on establishing clinical trial readiness for CMT neuropathies. These studies were also motivated by the failures of initial trials in CMT1A. However, CMTNS proved not to be sensitive enough for detecting meaningful changes within the study period as it only showed small annual progression in clinical trials [ 72 , 73 ].

Thus, at least several hundred patients would be needed in a double blinded trial to detect significant slowing of disease progression [ ]. Moreover, improvements in CMTNS score progression were even observed in the placebo groups [ 72 , ] unlike the previously available natural history data [ ].

Thus, careful choice of interpretable outcome measures and large enough participant numbers to ensure statistical power will be needed, as demonstrated by the ascorbic acid and PXT trials [ ]. Functional and patient-reported outcome PRO measures are additional tools currently being introduced to improve clinical trial design in CMT neuropathies. CMT-FOM has shown excellent inter-rater reliability [ ], however longitudinal studies will be necessary to determine its responsiveness and utility for clinical trials.

CMT-HI contains 18 themes to capture disease burden with a high internal consistency and test-retest reliability, that was able to discriminate between patient groups with different disease burden as well as between levels of disability as measured by the CMTES and the mobility-Disability Severity Index [ ]. Finally, wearable sensors are being tested as additional tools to measure daily activity outside the clinic as well as to evaluate gait and balance during the 6-min walk test 6MWT , timed up and go TUG , and the m walk of the CMT-FOM [ , ].

The 6MWT highly correlated with all previously used outcome measures. Progression of CMT neuropathies results in characteristic muscle atrophy and fat replacement of muscle tissue, providing a relevant outcome measure that can be directly assessed by neuroimaging.

Evaluation of both thigh and calf muscles will enhance the MRI sensitivity across different stages of the disease, as proximal thigh muscle involvement may continue to progress in a linear mode even after the distal calf muscle have reached an end-stage condition reducing their IMFA sensitivity to detect further changes.

Thus, adding the MRI for IMFA assessment of both proximal and distal limb muscles as a primary outcome measure in clinical trials will significantly improve the chance of detecting treatment response even with lower participant numbers in CMT1A and other more rare CMT forms.

Blood biomarkers provide another emerging tool that may complement clinical and MRI-based outcome measures. Molecular markers reflecting abnormalities in SCs, degenerating axons, or denervated muscle could serve as biomarkers for severity and progression in CMT neuropathies. Importantly, amelioration was demonstrated in animals treated with gene therapy, indicating that this may be a treatment-responsive biomarker as well. Further blood biomarkers are currently investigated using proteomics approaches.

Significant serum elevation of neural cell adhesion molecule-1 NCAM1 was shown in CMT1A patients as well as in patients with various forms of inflammatory neuropathies [ ]. NCAM-1 was shown to regulate synaptic reorganization after peripheral nerve injury suggesting an important role during regeneration [ ]. Thus, it may provide, along with NFL, a valuable marker of CMT pathology and should be considered for inclusion in future trial design. However, the natural history of progression of all these candidate blood biomarkers and how they correlate with other CMT outcome measures remains to be demonstrated in further longitudinal studies.

Horizontal aspects relevant to all CMT types are the establishment of longitudinal natural history data, which currently exist only for CMT1A, and the optimal clinical trial design tailored to the rarity of the specific CMT type [ ]. Multi-center trials will be needed and open label design may be necessary for very rare types. The initial clinical trials are likely to include only adults, while the inclusion of children may be considered from regulatory point of view only in CMT types with severe and early phenotypes.

Finally, we need to choose therapies with strong chances for success based on compelling biological evidence, as the number of trials that can be conducted is limited and failures can slow down an otherwise dynamic and promising path towards CMT treatments. The field of inherited neuropathies has progressed a long way from the clinicopathological era of the nineteenth century and the initial description of the disease by Charcot, Marie, and Tooth, with only supportive treatments, to the molecular genetic era in the last 30 years, and very recently entering an exciting new era of emerging treatments.

In this review we highlight how the diverse mechanisms of CMT neuropathies require a personalized medicine approach with disease-specific therapies, while final common pathways of axonal degeneration are also a major therapeutic target. This is a very active field with novel treatment approaches for several CMT forms currently in preclinical and in clinical trial stage.

Recent successful clinical translation of novel therapeutics in other neuromuscular disorders, including gene therapy, has provided further impetus to develop effective therapies for CMT patients as well.

Lessons learned from the initial clinical trials in CMT1A have stimulated the development of more comprehensive clinical evaluation tools, the discovery of sensitive disease biomarkers that could be treatment-responsive, and the optimization of clinical trial design. Thus, while many challenges remain in the path towards cures for CMT neuropathies, we have reasons to be hopeful for successful treatments in several CMT types in the near future.

National Center for Biotechnology Information , U. Int J Mol Sci. Published online Jun 3. Find articles by Marina Stavrou. Find articles by Irene Sargiannidou. Find articles by Elena Georgiou.

Find articles by Alexia Kagiava. Kleopas A. Author information Article notes Copyright and License information Disclaimer. Received Apr 28; Accepted May This article has been cited by other articles in PMC. Abstract Inherited neuropathies known as Charcot-Marie-Tooth CMT disease are genetically heterogeneous disorders affecting the peripheral nerves, causing significant and slowly progressive disability over the lifespan.

Keywords: Charcot-Marie-Tooth disease, inherited neuropathy, gene therapy, axonal degeneration, biomarkers. Gene Therapy Gene therapy refers to the delivery of genetic material to a subject mostly via viral vectors. Small Molecule Therapies Most drug therapy efforts for CMT neuropathies focus on the final common pathway of axonal degeneration, which occurs as a primary mechanism in axonal CMTs and as a secondary consequence in demyelinating CMT forms. Open in a separate window. Table 2 Summary of emerging treatment approaches for other CMT neuropathies.

Figure 1. Targeting Inflammatory Pathways to Treat CMT1X A potential alternative or complementary therapeutic target for CMT1X is the modification of inflammatory processes that are prominent at least in the mouse model of the disease, in which the presence of foamy macrophages is a characteristic feature of nerve pathology [ ]. Targeting the SARM1 Pathway Axonal degeneration is the hallmark of many neurological disorders, including CMT2A, and is considered to be a genetically encoded program of subcellular self-destruction.

Clinical Trial Readiness for CMT Neuropathies While there is a multitude of emerging treatments currently studied for CMT neuropathies, they remain mostly at the pre-clinical level and their clinical translation creates major challenges ahead.

Clinical Evaluation Tools Efforts over the last 10 years have focused on establishing clinical trial readiness for CMT neuropathies. MRI and Other Biomarkers Progression of CMT neuropathies results in characteristic muscle atrophy and fat replacement of muscle tissue, providing a relevant outcome measure that can be directly assessed by neuroimaging.

Summary and Future Perspectives The field of inherited neuropathies has progressed a long way from the clinicopathological era of the nineteenth century and the initial description of the disease by Charcot, Marie, and Tooth, with only supportive treatments, to the molecular genetic era in the last 30 years, and very recently entering an exciting new era of emerging treatments.

Institutional Review Board Statement Not applicable. Informed Consent Statement Not applicable. Conflicts of Interest The authors declare no conflict of interest. References 1. Kleopa K. Inherited neuropathies. Baets J. Recent advances in Charcot-Marie-Tooth disease.

Shy M. Peripheral Neuropathy. Hereditary motor and sensory neuropathies: An overview of clinical, genetic, electrophysiologic, and pathologic features; pp. Scherer S. Peripheral Neuropathies. In: Rosenberg N. Elsevier Inc. Bird T. Fridman V. CMT subtypes and disease burden in patients enrolled in the Inherited Neuropathies Consortium natural history study: A cross-sectional analysis. Murphy S.

Charcot—Marie—Tooth disease: Frequency of genetic subtypes and guidelines for genetic testing. Saporta A. Charcot-marie-tooth disease subtypes and genetic testing strategies. Wilmshurst J. Hereditary peripheral neuropathies of childhood: An overview for clinicians.

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Mathis S. Some new proposals for the classification of inherited myopathies. Rossor A. Clinical implications of genetic advances in Charcot-Marie-Tooth disease. Molecular mechanisms of inherited demyelinating neuropathies. Sargiannidou I. Gene therapy approaches targeting Schwann cells for demyelinating neuropathies. Brain Res. Stavrou M. Genetic mechanisms of peripheral nerve disease. Kantor B. Kagiava A. Intrathecal gene therapy in mouse models expressing CMT1X mutations.

Gene replacement therapy after neuropathy onset provides therapeutic benefit in a model of CMT1X. Intrathecal gene therapy rescues a model of demyelinating peripheral neuropathy. Schiza N. Gene replacement therapy in a model of Charcot-Marie-Tooth 4C neuropathy.

Lee J. Palfi S. Biffi A. Sahenk Z. NT-3 gene therapy for charcot-marie-tooth neuropathy. Serfecz J. Downregulation of the human peripheral myelin protein 22 gene by miRa in cellular models of Charcot—Marie—Tooth disease. Gene Ther. Morelli K. Gene therapy to promote regeneration in Charcot-Marie-Tooth disease.

Ozes B. AAV9-mediated Schwann cell-targeted gene therapy rescues a model of demyelinating neuropathy. Chi X. Safety of antisense oligonucleotide and siRNA-based therapeutics.

Drug Discov. Thenmozhi R. Pantera H. Regulation of the neuropathy-associated Pmp22 gene by a distal super-enhancer. Knauert M. Triplex forming oligonucleotides: Sequence-specific tools for gene targeting Human.

Makarova K. Smargon A. Cell Biol. Nucleic Acids Res. Gautier B. Nat Commun. Boutary S. Nizzardo M. Gene therapy rescues disease phenotype in a spinal muscular atrophy with respiratory distress type 1 SMARD1 mouse model.

Knabel M. Geisler S. Gene therapy targeting SARM1 blocks pathological axon degeneration in mice. Sancho S. Distal axonopathy in peripheral nerves of PMPmutant mice. Moss K. Targeting the programmed axon degeneration pathway as a potential therapeutic for Charcot-Marie-Tooth disease. Rossaert E. Lupski J. Valentijn L. Timmerman V. Matsunami N. Peripheral myelin protein—22 gene maps in the duplication in chromosome 17p Kiyosawa H. Snipes G. Authors can keep track of submitted papers on the move, and receive notification from chairs about their paper's status on the go.

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