SUMMARY:
This study provides proof of principle for a clinically translatable gene therapy approach to treat CMT1X before and after the onset of the neuropathy, even in the presence of endogenously expressed Golgi-retained Cx32 mutants.
TITLE:
Gene replacement therapy in two Golgi-retained CMT1X mutants before and after the onset of demyelinating neuropathy
DESCRIPTION:
X-linked Charcot-Marie-Tooth disease type 1 (CMT1X) is a demyelinating neuropathy resulting from loss-of-function mutations affecting the GJB1/connexin 32 (Cx32) gene. We previously showed functional and morphological improvement in Gjb1-null mice following AAV9-mediated delivery of human Cx32 driven by the myelin protein zero (Mpz) promoter in Schwann cells. However, CMT1X mutants may interfere with virally delivered wild-type (WT) Cx32. To confirm the efficacy of this vector also in the…
CONTENT:
Mol Ther Methods Clin Dev. 2023 Aug 2;30:377-393. doi: 10.1016/j.omtm.2023.07.011. eCollection 2023 Sep 14.
ABSTRACT
X-linked Charcot-Marie-Tooth disease type 1 (CMT1X) is a demyelinating neuropathy resulting from loss-of-function mutations affecting the GJB1 /connexin 32 (Cx32) gene. We previously showed functional and morphological improvement in Gjb1 -null mice following AAV9-mediated delivery of human Cx32 driven by the myelin protein zero (Mpz) promoter in Schwann cells. However, CMT1X mutants may interfere with virally delivered wild-type (WT) Cx32. To confirm the efficacy of this vector also in the presence of CMT1X mutants, we delivered AAV9-Mpz-GJB1 by lumbar intrathecal injection in R75W/Gjb1 -null and N175D/Gjb1 -null transgenic lines expressing Golgi-retained mutations, before and after the onset of the neuropathy. Widespread expression of virally delivered Cx32 was demonstrated in both genotypes. Re-establishment of WT Cx32 function resulted in improved muscle strength and increased sciatic nerve motor conduction velocities in all treated groups from both mutant lines when treated before as well as after the onset of the neuropathy. Furthermore, morphological analysis showed improvement of myelination and reduction of inflammation in lumbar motor roots and peripheral nerves. In conclusion, this study provides proof of principle for a clinically translatable gene therapy approach to treat CMT1X before and after the onset of the neuropathy, even in the presence of endogenously expressed Golgi-retained Cx32 mutants.
PMID:37645436 | PMC:PMC10460951 | DOI:10.1016/j.omtm.2023.07.011
SOURCE:
Molecular therapy. Methods & clinical development
TAGS:
CMT1X
CATEGORY:
Research
SUBCATEGORY:
n/a
DATE – PUBLISHED:
2023-08-02T07:36:13Z
DATE – DOI: 2023-08-02T07:36:13Z
DATE – PUBMED: 2023 Aug 2
DATE OUTPUT MATCHED: True
DATE – ADDED:
Wed, 30 Aug 2023 06:00:00 -0400
DATE – RETRIEVED:
08/30/23 06:44AM
2023-08-30T06:44:15-04:00
FEATURED IMAGE:
Media Uploaded (image/png)
IDENTIFIER:
pmid:37645436,pmc:PMC10460951,doi:10.1016/j.omtm.2023.07.011
PUBMED ID:
pubmed:37645436
DOI:
10.1016/j.omtm.2023.07.011
LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/37645436/
LINK – DOI:
https://doi.org/10.1016/j.omtm.2023.07.011
LINK – PUBLISHER:
https://linkinghub.elsevier.com/retrieve/pii/S2329050123001134
REFERENCES:
CMT Treatment Report, Urgent Research, 2023-08-30T06:44:15-04:00, https://www.cmttreatmentreport.com.
