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A translatable RNAi-driven gene therapy silences PMP22/Pmp22 genes and improves neuropathy in CMT1A mice

SUMMARY:
AAV9-miR871-driven silencing of PMP22 rescues a CMT1A model and provides proof of principle for treating CMT1A using a translatable gene therapy approach.

TITLE:
A translatable RNAi-driven gene therapy silences PMP22/Pmp22 genes and improves neuropathy in CMT1A mice

DESCRIPTION:
Charcot-Marie-Tooth disease type 1A (CMT1A), the most common inherited demyelinating peripheral neuropathy, is caused by PMP22 gene duplication. Over-expression of wild-type PMP22 in Schwann cells destabilizes the myelin sheath, leading to demyelination and ultimately to secondary axonal loss and disability. No treatments currently exist that modify the disease course. The most direct route to CMT1A therapy will involve reducing PMP22 to normal levels. To accomplish this, we developed a gene…

CONTENT:
J Clin Invest. 2022 May 17:e159814. doi: 10.1172/JCI159814. Online ahead of print.

ABSTRACT

Charcot-Marie-Tooth disease type 1A (CMT1A), the most common inherited demyelinating peripheral neuropathy, is caused by PMP22 gene duplication. Over-expression of wild-type PMP22 in Schwann cells destabilizes the myelin sheath, leading to demyelination and ultimately to secondary axonal loss and disability. No treatments currently exist that modify the disease course. The most direct route to CMT1A therapy will involve reducing PMP22 to normal levels. To accomplish this, we developed a gene therapy strategy to reduce PMP22 using novel artificial microRNAs targeting human and mouse PMP22/Pmp22 mRNAs. Our lead therapeutic microRNA, miR871, was packaged into an AAV9 vector and delivered by lumbar intrathecal injection into C61-het mice, a model of CMT1A. AAV9-miR871 efficiently transduced Schwann cells in C61-het peripheral nerves and reduced human and mouse PMP22/Pmp22 mRNA and protein levels. Treatment at early and late stages of the disease significantly improved multiple functional outcome measures and nerve conduction velocities. Furthermore, myelin pathology in lumbar roots and femoral motor nerves was ameliorated. Treated mice also showed reductions in circulating biomarkers of CMT1A. Taken together, our data demonstrate that AAV9-miR871-driven silencing of PMP22 rescues a CMT1A model and provides proof of principle for treating CMT1A using a translatable gene therapy approach.

PMID:35579942 | DOI:10.1172/JCI159814

SOURCE:
The Journal of clinical investigation

TAGS:
AAV9miR871driven silencing of PMP22

CATEGORY:
Research

SUBCATEGORY:
n/a

DATE – PUBLISHED:
2022-05-17T16:25:13Z

DATE – DOI: 2022-05-17T16:25:13Z
DATE – PUBMED: 2022 May 17
DATE OUTPUT MATCHED: True

DATE – ADDED:
Tue, 17 May 2022 06:00:00 -0400

DATE – RETRIEVED:
05/17/22 05:21PM
2022-05-17T17:21:36-04:00

FEATURED IMAGE:
Media Uploaded (image/png)

IDENTIFIER:
pmid:35579942,doi:10.1172/JCI159814

PUBMED ID:
pubmed:35579942

DOI:
10.1172/JCI159814

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/35579942/

LINK – DOI:
https://doi.org/10.1172/JCI159814

LINK – PUBLISHER:
http://www.jci.org/articles/view/159814

REFERENCES:
CMT Treatment Report, Urgent Research, 2022-05-17T17:21:36-04:00, https://www.cmttreatmentreport.com.

Molecular characterization of Turkish patients with demyelinating Charcot-Marie-Tooth disease

SUMMARY:
Many therapeutic strategy options including promising small-molecular compounds, gene replacement therapy, or disease-modifying therapies will soon be implemented in the clinical setting.

TITLE:
Molecular characterization of Turkish patients with demyelinating Charcot-Marie-Tooth disease

DESCRIPTION:
Charcot-Marie-Tooth (CMT) disease represents a distinct subgroup of inherited peripheral neuropathies with a significant prevalence throughout the world and manifests both phenotypic and genetic heterogeneity. Electrophysiological studies subclassify CMT mainly as demyelinating or axonal types. In this study, we investigated the molecular characteristics of a Turkish cohort of 23 probands out of 34 symptomatic demyelinating CMT individuals from January 2019 to December 2021. In order to identify…

CONTENT:
Neurogenetics. 2022 May 13. doi: 10.1007/s10048-022-00693-6. Online ahead of print.

ABSTRACT

Charcot-Marie-Tooth (CMT) disease represents a distinct subgroup of inherited peripheral neuropathies with a significant prevalence throughout the world and manifests both phenotypic and genetic heterogeneity. Electrophysiological studies subclassify CMT mainly as demyelinating or axonal types. In this study, we investigated the molecular characteristics of a Turkish cohort of 23 probands out of 34 symptomatic demyelinating CMT individuals from January 2019 to December 2021. In order to identify the underlying genetic cause, we applied a rational algorithm: PMP22 gene was initially analyzed for duplication, if PMP22-duplication testing was negative, other most causative genes (GJB1, MPZ) and PMP22 were then sequenced and if no variant was detected at aforementioned tests, whole exome sequencing (WES) test was finally performed. A total of 17 patients (≅ 74%; n = 23) were found to harbor a disease-causing variant in demyelinating CMT-related genes and among the variants, PMP22-duplication was the most frequent (≅ 41%). CMT1, CMTX, and CMT4 subtypes were manifested in ten, five, and two individuals respectively. GJB1 and SBF2 genes were the only detected genes associated with the CMTs other than CMT1. We also reported totally five novel variants: c.379A > C (p.Ile127Leu) and c.548G > T (p.Arg183Leu) variants in GJB1, c.988G > T (p.Glu330Ter) variant in NEFL, c.765_770delCCCTAT (p.Pro256_Ile257del) and c.2552A > C (p.His851Pro) variants in SBF2. As the understanding of pathophysiology and molecular mechanisms of CMT continues to evolve rapidly, many therapeutic strategy options including promising small-molecular compounds, gene replacement therapy, or disease-modifying therapies will soon be implemented in the clinical setting.

PMID:35562614 | DOI:10.1007/s10048-022-00693-6

SOURCE:
Neurogenetics

TAGS:
promising smallmolecular compounds gene replacement therapy diseasemodifying therapies

CATEGORY:
Research

SUBCATEGORY:
n/a

DATE – PUBLISHED:
2022-05-13T17:08:11Z

DATE – DOI: 2022-05-13T17:08:11Z
DATE – PUBMED: 2022 May 13
DATE OUTPUT MATCHED: True

DATE – ADDED:
Fri, 13 May 2022 06:00:00 -0400

DATE – RETRIEVED:
05/14/22 10:05AM
2022-05-14T10:05:09-04:00

FEATURED IMAGE:
Media Uploaded (image/png)

IDENTIFIER:
pmid:35562614,doi:10.1007/s10048-022-00693-6

PUBMED ID:
pubmed:35562614

DOI:
10.1007/s10048-022-00693-6

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/35562614/

LINK – DOI:
https://doi.org/10.1007/s10048-022-00693-6

LINK – PUBLISHER:
https://link.springer.com/10.1007/s10048-022-00693-6

REFERENCES:
CMT Treatment Report, Urgent Research, 2022-05-14T10:05:09-04:00, https://www.cmttreatmentreport.com.

Do different foot types affect the 6-min walk test capacity of younths with Charcot-Marie-Tooth neuropathy ?

SUMMARY:
Performance was decreased in youths with CMT in comparison to non-CMT. Contrary to what was expected, the cavus foot type did not show lower gait capacity than the flatfoot, suggesting that the types of feet alone did not determine differences in gait capacity within the CMT group.

TITLE:
Do different foot types affect the 6-min walk test capacity of younths with Charcot-Marie-Tooth neuropathy ?

DESCRIPTION:
CONCLUSIONS: These findings indicate that gait performance was decreased in youths with CMT in comparison to non-CMT. Contrary to what was expected, the cavus foot type did not show lower gait capacity than the flatfoot, suggesting that the types of feet alone did not determine differences in gait capacity within the CMT group.

CONTENT:
BMC Pediatr. 2022 May 13;22(1):277. doi: 10.1186/s12887-022-03338-7.

ABSTRACT

BACKGROUND: The present study aimed to assess the gait capacity of youths with Charcot Marie Tooth disease (CMT), considering the different foot postures as a grouping variable. METHODS: The total distance, the predicted distance, and gait velocity obtained during the six-minute walking test (6MWT) were compared between participants with and without CMT. In addition, part of the CMT group completed a 12-month follow-up. The study evaluated 63 participants (CMT group = 31; Non-CMT group = 32) aged 6 to 18, both sexes. Data included anthropometric measures, foot posture index (FPI), the distance (D6), percentage of predicted distance (%D6), and walking velocity(V) in 6MWT.

RESULTS: The D6% presented no significant difference between the types of feet in CMT or Non-CMT (p < 0.05, Kruskal Wallis test). CMT presented reduced values of D6, %D6, and V when compared to Non-CMT. CONCLUSIONS: These findings indicate that gait performance was decreased in youths with CMT in comparison to non-CMT. Contrary to what was expected, the cavus foot type did not show lower gait capacity than the flatfoot, suggesting that the types of feet alone did not determine differences in gait capacity within the CMT group. PMID:35562696 | DOI:10.1186/s12887-022-03338-7 SOURCE: BMC pediatrics TAGS: CMT CATEGORY: Research SUBCATEGORY: n/a DATE - PUBLISHED: 2022-05-13T07:04:58Z DATE - DOI: 2022-05-13T07:04:58Z DATE - PUBMED: 2022 May 13 DATE OUTPUT MATCHED: True DATE - ADDED: Fri, 13 May 2022 06:00:00 -0400 DATE - RETRIEVED: 05/14/22 10:05AM 2022-05-14T10:05:00-04:00 FEATURED IMAGE: Media Uploaded (image/png) IDENTIFIER: pmid:35562696,doi:10.1186/s12887-022-03338-7 PUBMED ID: pubmed:35562696 DOI: 10.1186/s12887-022-03338-7 LINK - PUBMED: https://pubmed.ncbi.nlm.nih.gov/35562696/ LINK - DOI: https://doi.org/10.1186/s12887-022-03338-7 LINK - PUBLISHER: https://bmcpediatr.biomedcentral.com/articles/10.1186/s12887-022-03338-7 REFERENCES: CMT Treatment Report, Urgent Research, 2022-05-14T10:05:00-04:00, https://www.cmttreatmentreport.com.

Effective treatment of advanced Hodgkin lymphoma with a modified BEACOPP regimen for a patient with demyelinating hereditary motor and sensory neuropathy type 1 (HMSN1)

SUMMARY:
The patient with Charcot-Marie-Tooth disease or HSMN1 and advanced Hodgkin lymphoma undergoing treatment with modified BEACOPP achieving complete remission without major aggravation of neurological symptoms.

TITLE:
Effective treatment of advanced Hodgkin lymphoma with a modified BEACOPP regimen for a patient with demyelinating hereditary motor and sensory neuropathy type 1 (HMSN1)

DESCRIPTION:
Treatment for Hodgkin lymphoma (HL) in adults comprises substantial risk of chemotherapy-induced peripheral neurotoxicity. Here, we describe the case of patient with Charcot-Marie-Tooth disease or HSMN1 and advanced Hodgkin lymphoma undergoing treatment with modified BEACOPP achieving complete remission without major aggravation of neurological symptoms.

CONTENT:
Clin Case Rep. 2022 May 5;10(5):e05766. doi: 10.1002/ccr3.5766. eCollection 2022 May.

ABSTRACT

Treatment for Hodgkin lymphoma (HL) in adults comprises substantial risk of chemotherapy-induced peripheral neurotoxicity. Here, we describe the case of patient with Charcot-Marie-Tooth disease or HSMN1 and advanced Hodgkin lymphoma undergoing treatment with modified BEACOPP achieving complete remission without major aggravation of neurological symptoms.

PMID:35540715 | PMC:PMC9069391 | DOI:10.1002/ccr3.5766

SOURCE:
Clinical case reports

TAGS:
HSMN1 BEACOPP

CATEGORY:
Research

SUBCATEGORY:
n/a

DATE – PUBLISHED:
2022-05-05T08:46:05Z

DATE – DOI: 2022-05-05T08:46:05Z
DATE – PUBMED: 2022 May 5
DATE OUTPUT MATCHED: True

DATE – ADDED:
Wed, 11 May 2022 06:00:00 -0400

DATE – RETRIEVED:
05/11/22 07:45AM
2022-05-11T07:45:17-04:00

FEATURED IMAGE:
Media Uploaded (image/png)

IDENTIFIER:
pmid:35540715,pmc:PMC9069391,doi:10.1002/ccr3.5766

PUBMED ID:
pubmed:35540715

DOI:
10.1002/ccr3.5766

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/35540715/

LINK – DOI:
https://doi.org/10.1002/ccr3.5766

LINK – PUBLISHER:
https://onlinelibrary.wiley.com/doi/10.1002/ccr3.5766

REFERENCES:
CMT Treatment Report, Urgent Research, 2022-05-11T07:45:17-04:00, https://www.cmttreatmentreport.com.

Structural insights into Charcot-Marie-Tooth disease-linked mutations in human GDAP1

SUMMARY:
CMT may arise from disruption of specific intra- and intermolecular interaction networks, leading to alterations in GDAP1 structure and stability, and eventually, insufficient motor and sensory neuron function.

TITLE:
Structural insights into Charcot-Marie-Tooth disease-linked mutations in human GDAP1

DESCRIPTION:
Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral polyneuropathy in humans, and its different subtypes are linked to mutations in dozens of different genes. Mutations in ganglioside-induced differentiation-associated protein 1 (GDAP1) cause two types of CMT, demyelinating CMT4A and axonal CMT2K. The GDAP1-linked CMT genotypes are mainly missense point mutations. Despite clinical profiling and in vivo studies on the mutations, the etiology of GDAP1-linked CMT is poorly…

CONTENT:
FEBS Open Bio. 2022 May 4. doi: 10.1002/2211-5463.13422. Online ahead of print.

ABSTRACT

Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral polyneuropathy in humans, and its different subtypes are linked to mutations in dozens of different genes. Mutations in ganglioside-induced differentiation-associated protein 1 (GDAP1) cause two types of CMT, demyelinating CMT4A and axonal CMT2K. The GDAP1-linked CMT genotypes are mainly missense point mutations. Despite clinical profiling and in vivo studies on the mutations, the etiology of GDAP1-linked CMT is poorly understood. Here, we describe the biochemical and structural properties of the Finnish founding CMT2K mutation H123R as well as CMT2K-linked R120W, both of which are autosomal dominant mutations. The disease variant proteins retain close to normal structure and solution behaviour, but both present a significant decrease in thermal stability. Using GDAP1 variant crystal structures, we identify a side chain interaction network between helices ⍺3, ⍺6, and ⍺7, which is affected by CMT mutations, as well as a hinge in the long helix ⍺6, which is linked to structural flexibility. Structural analysis of GDAP1 indicates that CMT may arise from disruption of specific intra- and intermolecular interaction networks, leading to alterations in GDAP1 structure and stability, and eventually, insufficient motor and sensory neuron function.

PMID:35509130 | DOI:10.1002/2211-5463.13422

SOURCE:
FEBS open bio

TAGS:
GDAP1

CATEGORY:
Research

SUBCATEGORY:
n/a

DATE – PUBLISHED:
2022-05-05T04:37:32Z

DATE – DOI: 2022-05-05T04:37:32Z
DATE – PUBMED: 2022 May 4
DATE OUTPUT MATCHED: True

DATE – ADDED:
Thu, 05 May 2022 06:00:00 -0400

DATE – RETRIEVED:
05/05/22 07:18AM
2022-05-05T07:18:13-04:00

FEATURED IMAGE:
Media Uploaded (image/png)

IDENTIFIER:
pmid:35509130,doi:10.1002/2211-5463.13422

PUBMED ID:
pubmed:35509130

DOI:
10.1002/2211-5463.13422

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/35509130/

LINK – DOI:
https://doi.org/10.1002/2211-5463.13422

LINK – PUBLISHER:
https://onlinelibrary.wiley.com/doi/10.1002/2211-5463.13422

REFERENCES:
CMT Treatment Report, Urgent Research, 2022-05-05T07:18:13-04:00, https://www.cmttreatmentreport.com.

Treatment with IFB-088 Improves Neuropathy in CMT1A and CMT1B Mice

SUMMARY:
IFB-088 reduces the amount of newly synthesized proteins entering the ER, allowing the protein quality control systems to better cope with the unfolded/misfolded protein and allowing myelination to progress.

TITLE:
Treatment with IFB-088 Improves Neuropathy in CMT1A and CMT1B Mice

DESCRIPTION:
Charcot-Marie-Tooth disease type 1A (CMT1A), caused by duplication of the peripheral myelin protein 22 (PMP22) gene, and CMT1B, caused by mutations in myelin protein zero (MPZ) gene, are the two most common forms of demyelinating CMT (CMT1), and no treatments are available for either. Prior studies of the MpzSer63del mouse model of CMT1B have demonstrated that protein misfolding, endoplasmic reticulum (ER) retention and activation of the unfolded protein response (UPR) contributed to the…

CONTENT:
Mol Neurobiol. 2022 Apr 30. doi: 10.1007/s12035-022-02838-y. Online ahead of print.

ABSTRACT

Charcot-Marie-Tooth disease type 1A (CMT1A), caused by duplication of the peripheral myelin protein 22 (PMP22) gene, and CMT1B, caused by mutations in myelin protein zero (MPZ) gene, are the two most common forms of demyelinating CMT (CMT1), and no treatments are available for either. Prior studies of the MpzSer63del mouse model of CMT1B have demonstrated that protein misfolding, endoplasmic reticulum (ER) retention and activation of the unfolded protein response (UPR) contributed to the neuropathy. Heterozygous patients with an arginine to cysteine mutation in MPZ (MPZR98C) develop a severe infantile form of CMT1B which is modelled by MpzR98C/ + mice that also show ER stress and an activated UPR. C3-PMP22 mice are considered to effectively model CMT1A. Altered proteostasis, ER stress and activation of the UPR have been demonstrated in mice carrying Pmp22 mutations. To determine whether enabling the ER stress/UPR and readjusting protein homeostasis would effectively treat these models of CMT1B and CMT1A, we administered Sephin1/IFB-088/icerguestat, a UPR modulator which showed efficacy in the MpzS63del model of CMT1B, to heterozygous MpzR98C and C3-PMP22 mice. Mice were analysed by behavioural, neurophysiological, morphological and biochemical measures. Both MpzR98C/ + and C3-PMP22 mice improved in motor function and neurophysiology. Myelination, as demonstrated by g-ratios and myelin thickness, improved in CMT1B and CMT1A mice and markers of UPR activation returned towards wild-type values. Taken together, our results demonstrate the capability of IFB-088 to treat a second mouse model of CMT1B and a mouse model of CMT1A, the most common form of CMT. Given the recent benefits of IFB-088 treatment in amyotrophic lateral sclerosis and multiple sclerosis animal models, these data demonstrate its potential in managing UPR and ER stress for multiple mutations in CMT1 as well as in other neurodegenerative diseases. (Left panel) the accumulation of overexpressed PMP22 or misfolded mutant P0 in the Schwann cell endoplasmic reticulum (ER) leads to overwhelming of the degradative capacity, activation of ER-stress mechanisms, and myelination impairment. (Right panel) by prolonging eIF2α phosphorylation, IFB-088 reduces the amount of newly synthesized proteins entering the ER, allowing the protein quality control systems to better cope with the unfolded/misfolded protein and allowing myelination to progress.

PMID:35501630 | DOI:10.1007/s12035-022-02838-y

SOURCE:
Molecular neurobiology

TAGS:
IFB-088

CATEGORY:
Research

SUBCATEGORY:
n/a

DATE – PUBLISHED:
2022-05-02T16:29:49Z

DATE – DOI: 2022-05-02T16:29:49Z
DATE – PUBMED: 2022 Apr 30
DATE OUTPUT MATCHED: True

DATE – ADDED:
Mon, 02 May 2022 06:00:00 -0400

DATE – RETRIEVED:
05/03/22 01:21AM
2022-05-03T01:21:41-04:00

FEATURED IMAGE:
Media Uploaded (image/png)

IDENTIFIER:
pmid:35501630,doi:10.1007/s12035-022-02838-y

PUBMED ID:
pubmed:35501630

DOI:
10.1007/s12035-022-02838-y

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/35501630/

LINK – DOI:
https://doi.org/10.1007/s12035-022-02838-y

LINK – PUBLISHER:
https://link.springer.com/10.1007/s12035-022-02838-y

REFERENCES:
CMT Treatment Report, Urgent Research, 2022-05-03T01:21:41-04:00, https://www.cmttreatmentreport.com.

Novel de novo POLR3B mutations responsible for demyelinating Charcot-Marie-Tooth disease in Japan

SUMMARY:
POLR3B mutations should be added to the CMT-related gene panel for comprehensive genetic screening.

TAG:
#POLR3B

TITLE:
Novel de novo POLR3B mutations responsible for demyelinating Charcot-Marie-Tooth disease in Japan

DESCRIPTION:
CONCLUSION: Our study is the third report on patients with demyelinating CMT harboring heterozygous POLR3B mutations and verifies the pathogenicity of POLR3B mutations in CMT. Although extremely rare in our large Japanese case series, POLR3B mutations should be added to the CMT-related gene panel for comprehensive genetic screening, particularly for patients with early-onset demyelinating CMT.

CONTENT:
Ann Clin Transl Neurol. 2022 Apr 28. doi: 10.1002/acn3.51555. Online ahead of print.

ABSTRACT

BACKGROUND: Biallelic POLR3B mutations cause a rare hypomyelinating leukodystrophy. De novo POLR3B heterozygous mutations were recently associated with afferent ataxia, spasticity, variable intellectual disability, and epilepsy, and predominantly demyelinating sensorimotor peripheral neuropathy.

METHODS: We performed whole-exome sequencing (WES) of DNA samples from 804 Charcot-Marie-Tooth (CMT) cases that could not be genetically diagnosed by DNA-targeted resequencing microarray using next-generation sequencers. Using WES data, we analyzed the POLR3B mutations and confirmed their clinical features.

RESULTS: We identified de novo POLR3B heterozygous missense mutations in two patients. These patients presented with early-onset demyelinating sensorimotor neuropathy without ataxia, spasticity, or cognitive impairment. Patient 1 showed mild cerebellar atrophy and spinal cord atrophy on magnetic resonance imaging and eventually died of respiratory failure in her 50s. We classified these mutations as pathogenic based on segregation studies, comparison with control database, and in silico analysis.

CONCLUSION: Our study is the third report on patients with demyelinating CMT harboring heterozygous POLR3B mutations and verifies the pathogenicity of POLR3B mutations in CMT. Although extremely rare in our large Japanese case series, POLR3B mutations should be added to the CMT-related gene panel for comprehensive genetic screening, particularly for patients with early-onset demyelinating CMT.

PMID:35482004 | DOI:10.1002/acn3.51555

SOURCE:
Annals of clinical and translational neurology

CATEGORY:
Research

SUBCATEGORY:
Clinically Relevant

DATE – PUBLISHED:
2022-04-28T14:57:46Z

DATE – DOI: 2022-04-28T14:57:46Z
DATE – PUBMED: 2022 Apr 28
DATE OUTPUT MATCHED: True

DATE – ADDED:
Thu, 28 Apr 2022 06:00:00 -0400

DATE – RETRIEVED:
04/28/22 01:25PM
2022-04-28T13:25:22-04:00

IDENTIFIER:
pmid:35482004,doi:10.1002/acn3.51555

PUBMED ID:
pubmed:35482004

DOI:
10.1002/acn3.51555

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/35482004/

LINK – DOI:
https://doi.org/10.1002/acn3.51555

LINK – PUBLISHER:
https://onlinelibrary.wiley.com/doi/10.1002/acn3.51555

REFERENCES:
CMT Treatment Report, Urgent Research, 2022-04-28T13:25:22-04:00, https://www.cmttreatmentreport.com.

Generation of a human induced pluripotent stem cell (iPSC) line (JUCTCi019-A) from a patient with Charcot-Marie-Tooth disease type 2A2 (CMT2A2) due to a heterozygous missense substitution c.2119C > T (p.Arg707Trp) in MFN2 gene

SUMMARY:
This iPSC line represents an ideal source for disease modelling and drug development of CMT2A2 disease.

TAG:
#CMT2A2

TITLE:
Generation of a human induced pluripotent stem cell (iPSC) line (JUCTCi019-A) from a patient with Charcot-Marie-Tooth disease type 2A2 (CMT2A2) due to a heterozygous missense substitution c.2119C > T (p.Arg707Trp) in MFN2 gene

DESCRIPTION:
Charcot-Marie-Tooth disease (CMT) is an inherited neurological disorder characterized by the progressive damage of the peripheral nerves. We generated a human induced pluripotent stem cell (iPSC) line JUCTCi019-A using dermal fibroblasts-derived from a 50-year-old CMT2A2 patient carrying a heterozygous missense substitution c.2119C > T (p.Arg707Trp) in the MFN2 gene. Fibroblasts were reprogrammed by Sendai viruses encoding for the reprogramming factors: OCT4, SOX2, KLF4 and c-MYC….

CONTENT:
Stem Cell Res. 2022 Apr 12;62:102786. doi: 10.1016/j.scr.2022.102786. Online ahead of print.

ABSTRACT

Charcot-Marie-Tooth disease (CMT) is an inherited neurological disorder characterized by the progressive damage of the peripheral nerves. We generated a human induced pluripotent stem cell (iPSC) line JUCTCi019-A using dermal fibroblasts-derived from a 50-year-old CMT2A2 patient carrying a heterozygous missense substitution c.2119C > T (p.Arg707Trp) in the MFN2 gene. Fibroblasts were reprogrammed by Sendai viruses encoding for the reprogramming factors: OCT4, SOX2, KLF4 and c-MYC. Characterization showed normal iPSC morphology and karyotype, expression of pluripotency markers and differentiation into three-germ layers. This iPSC line represents an ideal source for disease modelling and drug development of CMT2A2 disease.

PMID:35468369 | DOI:10.1016/j.scr.2022.102786

SOURCE:
Stem cell research

CATEGORY:
Research

SUBCATEGORY:
Clinically Relevant

DATE – PUBLISHED:
2022-04-12T17:59:21Z

DATE – DOI: 2022-04-12T17:59:21Z
DATE – PUBMED: 2022 Apr 12
DATE OUTPUT MATCHED: True

DATE – ADDED:
Mon, 25 Apr 2022 06:00:00 -0400

DATE – RETRIEVED:
04/26/22 01:26AM
2022-04-26T01:26:11-04:00

IDENTIFIER:
pmid:35468369,doi:10.1016/j.scr.2022.102786

PUBMED ID:
pubmed:35468369

DOI:
10.1016/j.scr.2022.102786

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/35468369/

LINK – DOI:
https://doi.org/10.1016/j.scr.2022.102786

LINK – PUBLISHER:
https://linkinghub.elsevier.com/retrieve/pii/S1873506122001350

REFERENCES:
CMT Treatment Report, Urgent Research, 2022-04-26T01:26:11-04:00, https://www.cmttreatmentreport.com.

Dosage effects of PMP22 on nonmyelinating Schwann cells in hereditary neuropathy with liability to pressure palsies

SUMMARY:
PMP22 dosage affects nonmyelinating as well as myelinating Schwann cells.

TITLE:
Dosage effects of PMP22 on nonmyelinating Schwann cells in hereditary neuropathy with liability to pressure palsies

DESCRIPTION:
Focal thickening of the myelin sheath, also known as tomacula, is a characteristic pathological feature of patients with hereditary neuropathy with liability to pressure palsies (HNPP). However, a deeper understanding of the pathology underlying unmyelinated fibers and nonmyelinating Schwann cells is required. Electron microscopic examination of sural nerve biopsy specimens was performed for 14 HNPP patients with peripheral myelin protein 22 (PMP22) deletion, and their results were compared to…

CONTENT:
Neuromuscul Disord. 2022 Apr 9:S0960-8966(22)00102-X. doi: 10.1016/j.nmd.2022.04.002. Online ahead of print.

ABSTRACT

Focal thickening of the myelin sheath, also known as tomacula, is a characteristic pathological feature of patients with hereditary neuropathy with liability to pressure palsies (HNPP). However, a deeper understanding of the pathology underlying unmyelinated fibers and nonmyelinating Schwann cells is required. Electron microscopic examination of sural nerve biopsy specimens was performed for 14 HNPP patients with peripheral myelin protein 22 (PMP22) deletion, and their results were compared to 12 normal controls and 14 Charcot-Marie-Tooth disease type 1A (CMT1A) patients with PMP22 duplication. The number of unmyelinated axons in a single axon-containing nonmyelinating Schwann cell subunit in the HNPP group significantly increased compared with that in normal controls (1.99 ± 0.66 vs. 1.57 ± 0.52, p < 0.05). Conversely, these numbers significantly decreased in the CMT1A group compared with those in normal controls (1.16 ± 0.16, p < 0.05). Some unmyelinated axons in patients with HNPP were incompletely surrounded by the cytoplasm of Schwann cells, almost as if the Schwann cells failed to form mesaxons; such failure in mesaxon formation was not observed in normal controls or in patients with CMT1A. These findings suggest that PMP22 dosage affects nonmyelinating as well as myelinating Schwann cells. PMID:35501275 | DOI:10.1016/j.nmd.2022.04.002 SOURCE: Neuromuscular disorders : NMD TAGS: PMP22 CATEGORY: Research SUBCATEGORY: n/a DATE - PUBLISHED: 2022-04-09T06:12:08Z DATE - DOI: 2022-04-09T06:12:08Z DATE - PUBMED: 2022 Apr 9 DATE OUTPUT MATCHED: True DATE - ADDED: Mon, 02 May 2022 06:00:00 -0400 DATE - RETRIEVED: 05/03/22 01:21AM 2022-05-03T01:21:41-04:00 FEATURED IMAGE: Media Uploaded (image/png) IDENTIFIER: pmid:35501275,doi:10.1016/j.nmd.2022.04.002 PUBMED ID: pubmed:35501275 DOI: 10.1016/j.nmd.2022.04.002 LINK - PUBMED: https://pubmed.ncbi.nlm.nih.gov/35501275/ LINK - DOI: https://doi.org/10.1016/j.nmd.2022.04.002 LINK - PUBLISHER: https://linkinghub.elsevier.com/retrieve/pii/S096089662200102X REFERENCES: CMT Treatment Report, Urgent Research, 2022-05-03T01:21:41-04:00, https://www.cmttreatmentreport.com.

Curcumin and Ethanol Effects in Trembler-J Schwann Cell Culture

SUMMARY:
The analysis of the effects of the vehicle itself is an essential and inescapable step to comprehensibly assess the effects and full potential of curcumin treatment for therapeutic purposes.

TAG:
#curcumin

TITLE:
Curcumin and Ethanol Effects in Trembler-J Schwann Cell Culture

DESCRIPTION:
Charcot-Marie-Tooth (CMT) syndrome is the most common progressive human motor and sensory peripheral neuropathy. CMT type 1E is a demyelinating neuropathy affecting Schwann cells due to peripheral-myelin-protein-22 (PMP22) mutations, modelized by Trembler-J mice. Curcumin, a natural polyphenol compound obtained from turmeric (Curcuma longa), exhibits dose- and time-varying antitumor, antioxidant and neuroprotective properties, however, the neurotherapeutic actions of curcumin remain elusive….

CONTENT:
Biomolecules. 2022 Mar 29;12(4):515. doi: 10.3390/biom12040515.

ABSTRACT

Charcot-Marie-Tooth (CMT) syndrome is the most common progressive human motor and sensory peripheral neuropathy. CMT type 1E is a demyelinating neuropathy affecting Schwann cells due to peripheral-myelin-protein-22 (PMP22) mutations, modelized by Trembler-J mice. Curcumin, a natural polyphenol compound obtained from turmeric (Curcuma longa ), exhibits dose- and time-varying antitumor, antioxidant and neuroprotective properties, however, the neurotherapeutic actions of curcumin remain elusive. Here, we propose curcumin as a possible natural treatment capable of enhancing cellular detoxification mechanisms, resulting in an improvement of the neurodegenerative Trembler-J phenotype. Using a refined method for obtaining enriched Schwann cell cultures, we evaluated the neurotherapeutic action of low dose curcumin treatment on the PMP22 expression, and on the chaperones and autophagy/mammalian target of rapamycin (mTOR) pathways in Trembler-J and wild-type genotypes. In wild-type Schwann cells, the action of curcumin resulted in strong stimulation of the chaperone and macroautophagy pathway, whereas the modulation of ribophagy showed a mild effect. However, despite the promising neuroprotective effects for the treatment of neurological diseases, we demonstrate that the action of curcumin in Trembler-J Schwann cells could be impaired due to the irreversible impact of ethanol used as a common curcumin vehicle necessary for administration. These results contribute to expanding our still limited understanding of PMP22 biology in neurobiology and expose the intrinsic lability of the neurodegenerative Trembler-J genotype. Furthermore, they unravel interesting physiological mechanisms of cellular resilience relevant to the pharmacological treatment of the neurodegenerative Tremble J phenotype with curcumin and ethanol. We conclude that the analysis of the effects of the vehicle itself is an essential and inescapable step to comprehensibly assess the effects and full potential of curcumin treatment for therapeutic purposes.

PMID:35454103 | DOI:10.3390/biom12040515

SOURCE:
Biomolecules

CATEGORY:
Research

SUBCATEGORY:
Clinically Relevant

DATE – PUBLISHED:
2022-03-30T02:24:22Z

DATE – DOI: 2022-03-30T02:24:22Z
DATE – PUBMED: 2022 Mar 29
DATE OUTPUT MATCHED: True

DATE – ADDED:
Sat, 23 Apr 2022 06:00:00 -0400

DATE – RETRIEVED:
04/23/22 09:21AM
2022-04-23T09:21:35-04:00

IDENTIFIER:
pmid:35454103,doi:10.3390/biom12040515

PUBMED ID:
pubmed:35454103

DOI:
10.3390/biom12040515

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/35454103/

LINK – DOI:
https://doi.org/10.3390/biom12040515

LINK – PUBLISHER:
https://www.mdpi.com/2218-273X/12/4/515

REFERENCES:
CMT Treatment Report, Urgent Research, 2022-04-23T09:21:35-04:00, https://www.cmttreatmentreport.com.

Neuropathic pain in Charcot-Marie-Tooth Disease

SUMMARY:
NP prevalence varies among CMTs subtypes and is mainly related to Aδ fibers impairment.

TAG:
#NP

TITLE:
Neuropathic pain in Charcot-Marie-Tooth Disease

DESCRIPTION:
CONCLUSIONS: NP prevalence varies among CMTs subtypes and is mainly related to Aδ fibers impairment.

CONTENT:
Eur J Pain. 2022 Feb 7. doi: 10.1002/ejp.1922. Online ahead of print.

ABSTRACT

BACKGROUND: Pain, either nociceptive or neuropathic (NP), is a common symptom in Charcot-Marie-Tooth (CMT) disease.

METHODS: We investigated small fibers involvement and its correlation with pain in different CMT subtypes through a systematic clinical and neurophysiological study. We enrolled 50 patients: 19 with duplication of PMP22 (CMT1A), 11 with mutation of MPZ (CMT1B, CMT2I/J or CMTDID), 12 with mutation of GJB1 (CMTX1) and 8 with mutation of MFN2 (CMT2A and CMT2A2B). Pain was rated with the 11-point Numerical Rating Scale and characterized through Neuropathic Pain Symptoms Inventory). Laser evoked potentials (LEPs) were recorded after right foot and hand stimulation and N2-P2 complex amplitude and latency were compared with those of 41 controls.

RESULTS: Overall pain prevalence was 36%. NP was present in 14,6 % of patients, with a length-dependent distribution in 85,7% of cases and it was significantly more frequent in CMT1A (p<0,001). Aδ fibers involvement greatly varies between CMT subtypes, reflecting differences in molecular pathology and pathophysiologic mechanisms. Prolonged N2 latency from foot stimulation was noted in 11 CMT1A patients, 5 of which report NP. MPZ-CMTs displayed different neurophysiological phenotypes and a very low prevalence of NP. LEPs were normal in all but one CMTX1 patients, although lower limbs N2-P2 amplitude was significantly reduced in males (p=0,043). MFN2-CMTs were NP free and LEPs recordings were all normal. NP strictly correlated with LEPs alterations (p=0,017). CONCLUSIONS: NP prevalence varies among CMTs subtypes and is mainly related to Aδ fibers impairment. PMID:35129250 | DOI:10.1002/ejp.1922 SOURCE: European journal of pain (London, England) CATEGORY: Research SUBCATEGORY: Clinically Relevant DATE - PUBLISHED: 2022-02-07T11:37:04Z DATE - DOI: 2022-02-07T11:37:04Z DATE - PUBMED: 2022 Feb 7 DATE OUTPUT MATCHED: True DATE - ADDED: Mon, 07 Feb 2022 06:00:00 -0500 DATE - RETRIEVED: 02/07/22 04:02PM 2022-02-07T16:02:06-05:00 IDENTIFIER: pmid:35129250,doi:10.1002/ejp.1922 PUBMED ID: pubmed:35129250 DOI: 10.1002/ejp.1922 LINK - PUBMED: https://pubmed.ncbi.nlm.nih.gov/35129250/ LINK - DOI: https://doi.org/10.1002/ejp.1922 LINK - PUBLISHER: https://onlinelibrary.wiley.com/doi/10.1002/ejp.1922 REFERENCES: CMT Treatment Report, Urgent Research, 2022-02-07T16:02:06-05:00, https://www.cmttreatmentreport.com.

Cytokines secreted by mesenchymal stem cells reduce demyelination in an animal model of Charcot-Marie-Tooth disease

SUMMARY:
Further elucidation of the underlying mechanisms of GDF-15 and AREG in myelination might provide a robust basis for the development of effective therapies against demyelinating CMT.

ALT SUMMARY:

GDF-15, AREG

TITLE:
Cytokines secreted by mesenchymal stem cells reduce demyelination in an animal model of Charcot-Marie-Tooth disease

DESCRIPTION:
CONCLUSIONS: Our findings demonstrated that WJ-MSCs alleviate the demyelinating phenotype of CMT via the secretion of several cytokines. Further elucidation of the underlying mechanisms of GDF-15 and AREG in myelination might provide a robust basis for the development of effective therapies against demyelinating CMT.

CONTENT:
Biochem Biophys Res Commun. 2022 Jan 29;597:1-7. doi: 10.1016/j.bbrc.2022.01.098. Online ahead of print.

ABSTRACT

INTRODUCTION: Demyelinating Charcot-Marie-Tooth disease (CMT) is caused by mutations in the genes that encode myelinating proteins or their transcription factors. Our study thus sought to assess the therapeutic effects of cytokines secreted from mesenchymal stem cells (MSCs) on this disease.

METHODS: The therapeutic potential of Wharton’s jelly MSCs (WJ-MSCs) and cytokines secreted by WJ-MSCs was evaluated on Schwann cells (SCs) exhibiting demyelination features, as well as a mouse model of demyelinating CMT.

RESULTS: Co-culture with WJ-MSC protected PMP22-overexpressing SCs from apoptotic cell death. Using a cytokine array, the secretion of growth differentiation factor-15 (GDF-15) and amphiregulin (AREG) was found to be elevated in WJ-MSCs when co-incubated with the PMP22-overexpressing SCs. Administration of both cytokines into trembler-J (Tr-J) mice, an animal model of CMT, significantly enhanced motor nerve conduction velocity compared to the control group. More importantly, this treatment alleviated the demyelinating phenotype of Tr-J mice, as demonstrated by an improvement in the mean diameter and g-ratio of the myelinated axons.

CONCLUSIONS: Our findings demonstrated that WJ-MSCs alleviate the demyelinating phenotype of CMT via the secretion of several cytokines. Further elucidation of the underlying mechanisms of GDF-15 and AREG in myelination might provide a robust basis for the development of effective therapies against demyelinating CMT.

PMID:35121177 | DOI:10.1016/j.bbrc.2022.01.098

SOURCE:
Biochemical and biophysical research communications

CATEGORY:
Research

SUBCATEGORY:
Clinically Relevant

DATE – PUBLISHED:
2022-01-29T01:39:49Z

DATE – DOI: 2022-01-29T01:39:49Z
DATE – PUBMED: 2022 Jan 29
DATE OUTPUT MATCHED: True

DATE – ADDED:
Sat, 05 Feb 2022 06:00:00 -0500

DATE – RETRIEVED:
02/06/22 08:55AM
2022-02-06T08:55:55-05:00

IDENTIFIER:
pmid:35121177,doi:10.1016/j.bbrc.2022.01.098

PUBMED ID:
pubmed:35121177

DOI:
10.1016/j.bbrc.2022.01.098

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/35121177/

LINK – DOI:
https://doi.org/10.1016/j.bbrc.2022.01.098

LINK – PUBLISHER:
https://linkinghub.elsevier.com/retrieve/pii/S0006291X22001309

REFERENCES:
CMT Treatment Report, Urgent Research, 2022-02-06T08:55:55-05:00, https://www.cmttreatmentreport.com.

SARM1 Knockout Does Not Rescue Neuromuscular Phenotypes in a Charcot-Marie-Tooth Disease Type 1A Mouse Model

SUMMARY:
The study found that the mice served in CMT1A mice are likely caused primarily by prolonged dysmyelination.

TITLE:
SARM1 Knockout Does Not Rescue Neuromuscular Phenotypes in a Charcot-Marie-Tooth Disease Type 1A Mouse Model

DESCRIPTION:
BACKGROUND AND AIMS: Charcot-Marie-Tooth disease Type 1A (CMT1A) is caused by duplication of the PMP22 gene and is the most common inherited peripheral neuropathy. Although CMT1A is a dysmyelinating peripheral neuropathy, secondary axon degeneration has been suggested to drive functional deficits in patients. Given that SARM1 knockout is a potent inhibitor of the programmed axon degeneration pathway, we asked whether SARM1 knockout rescues neuromuscular phenotypes in CMT1A model (C3-PMP) mice.

CONTENT:
J Peripher Nerv Syst. 2022 Feb 8. doi: 10.1111/jns.12483. Online ahead of print.

ABSTRACT

BACKGROUND AND AIMS: Charcot-Marie-Tooth disease Type 1A (CMT1A) is caused by duplication of the PMP22 gene and is the most common inherited peripheral neuropathy. Although CMT1A is a dysmyelinating peripheral neuropathy, secondary axon degeneration has been suggested to drive functional deficits in patients. Given that SARM1 knockout is a potent inhibitor of the programmed axon degeneration pathway, we asked whether SARM1 knockout rescues neuromuscular phenotypes in CMT1A model (C3-PMP) mice.

METHODS: CMT1A mice were bred with SARM1 knockout mice to generate CMT1A/SARM1 -/- mice. A series of behavioral assays were employed to evaluate motor and sensorimotor function. Electrophysiological and histological studies of the tibial branch of the sciatic nerve were performed. Additionally, gastrocnemius and soleus muscle morphology were also evaluated histologically.

RESULTS: Although clear behavioral and electrophysiological deficits were observed in CMT1A model mice, SARM1 knockout conferred no significant improvement. Nerve morphometry revealed predominantly myelin deficits in CMT1A model mice and SARM1 knockout yielded no improvement in all nerve morphometry measures. Similarly, muscle morphometry deficits in CMT1A model mice were not improved by SARM1 knockout.

INTERPRETATION: Our findings demonstrate that programmed axon degeneration pathway inhibition does not provide therapeutic benefit in CMT1A model mice. Our results indicate that the clinical phenotypes observed in CMT1A mice are likely caused primarily by prolonged dysmyelination, motivate further investigation into mechanisms of dysmyelination in these mice and necessitate the development of improved CMT1A rodent models that recapitulate the secondary axon degeneration observed in patients.

PMID:35137510 | DOI:10.1111/jns.12483

SOURCE:
Journal of the peripheral nervous system : JPNS

TAGS:
#CMT1A

CATEGORY:
Research

SUBCATEGORY:
n/a

DATE – PUBLISHED:
2022-01-29T01:39:49Z

DATE – DOI: 2022-01-29T01:39:49Z
DATE – PUBMED: 2022 Feb 8
DATE OUTPUT MATCHED: True

DATE – ADDED:
Wed, 09 Feb 2022 06:00:00 -0500

DATE – RETRIEVED:
05/02/22 02:45AM
2022-05-02T02:45:07-04:00

FEATURED IMAGE:
Media Uploaded (image/png)

IDENTIFIER:
pmid:35137510,doi:10.1111/jns.12483

PUBMED ID:
pubmed:35137510

DOI:
10.1111/jns.12483

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/35137510/

LINK – DOI:
https://doi.org/10.1111/jns.12483

LINK – PUBLISHER:
https://linkinghub.elsevier.com/retrieve/pii/S0006291X22001309

REFERENCES:
CMT Treatment Report, Urgent Research, 2022-05-02T02:45:07-04:00, https://www.cmttreatmentreport.com.

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