SUMMARY:
Taken together, our results provide a proof of concept for an effective and potentially translatable gene replacement therapy for CMT4C treatment.
TITLE:
AAV9-mediated SH3TC2 gene replacement therapy targeted to Schwann cells for the treatment of CMT4C
DESCRIPTION:
Type 4C Charcot-Marie-Tooth (CMT4C) demyelinating neuropathy is caused by autosomal recessive SH3TC2 gene mutations. SH3TC2 is highly expressed in myelinating Schwann cells. CMT4C is a childhood-onset progressive disease without effective treatment. Here we generated a gene therapy for CMT4C mediated by an adeno-associated viral 9 vector (AAV9) to deliver the human SH3TC2 gene in the Sh3tc2^(-/-) mouse model of CMT4C. We used a minimal fragment of the myelin protein zero (Mpz) promoter (miniMpz)…
CONTENT:
Mol Ther. 2023 Aug 28:S1525-0016(23)00452-5. doi: 10.1016/j.ymthe.2023.08.020. Online ahead of print.
ABSTRACT
Type 4C Charcot-Marie-Tooth (CMT4C) demyelinating neuropathy is caused by autosomal recessive SH3TC2 gene mutations. SH3TC2 is highly expressed in myelinating Schwann cells. CMT4C is a childhood-onset progressive disease without effective treatment. Here we generated a gene therapy for CMT4C mediated by an adeno-associated viral 9 vector (AAV9) to deliver the human SH3TC2 gene in the Sh3tc2-/- mouse model of CMT4C. We used a minimal fragment of the myelin protein zero (Mpz) promoter (miniMpz) which was cloned and validated to achieve Schwann cell-targeted expression of SH3TC2. Following the demonstration of AAV9-miniMpz.SH3TC2myc vector efficacy to re-establish SH3TC2 expression in the PNS, we performed an early as well as a delayed treatment trial in Sh3tc2-/- mice. We demonstrate both after early as well as following late treatment improvements in multiple motor performance tests and nerve conduction velocities. Moreover, treatment led to normalization of the organization of the nodes of Ranvier, which is typically deficient in CMT4C patients and Sh3tc2-/- mice, along with reduced ratios of demyelinated fibers, increased myelin thickness and reduced g-ratios at both time points of intervention. Taken together, our results provide a proof of concept for an effective and potentially translatable gene replacement therapy for CMT4C treatment.
PMID:37641403 | DOI:10.1016/j.ymthe.2023.08.020
SOURCE:
Molecular therapy : the journal of the American Society of Gene Therapy
TAGS:
CMT4C
CATEGORY:
Research
SUBCATEGORY:
n/a
DATE – PUBLISHED:
2023-08-28T05:57:43Z
DATE – DOI: 2023-08-28T05:57:43Z
DATE – PUBMED: 2023 Aug 28
DATE OUTPUT MATCHED: True
DATE – ADDED:
Tue, 29 Aug 2023 06:00:00 -0400
DATE – RETRIEVED:
08/29/23 06:40AM
2023-08-29T06:40:00-04:00
FEATURED IMAGE:
Media Uploaded (image/png)
IDENTIFIER:
pmid:37641403,doi:10.1016/j.ymthe.2023.08.020
PUBMED ID:
pubmed:37641403
DOI:
10.1016/j.ymthe.2023.08.020
LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/37641403/
LINK – DOI:
https://doi.org/10.1016/j.ymthe.2023.08.020
LINK – PUBLISHER:
https://linkinghub.elsevier.com/retrieve/pii/S1525001623004525
REFERENCES:
CMT Treatment Report, Urgent Research, 2023-08-29T06:40:00-04:00, https://www.cmttreatmentreport.com.
