Skip to main content
Advertisement
  • Neurology.org
  • Journals
    • Neurology
    • Clinical Practice
    • Education
    • Genetics
    • Neuroimmunology & Neuroinflammation
  • Online Sections
    • Neurology Video Journal Club
    • Diversity, Equity, & Inclusion (DEI)
    • Neurology: Clinical Practice Accelerator
    • Practice Buzz
    • Practice Current
    • Residents & Fellows
    • Without Borders
  • Collections
    • COVID-19
    • Disputes & Debates
    • Health Disparities
    • Infographics
    • Neurology Future Forecasting Series
    • Null Hypothesis
    • Patient Pages
    • Topics A-Z
    • Translations
    • UDDA Revision Series
  • Podcast
  • CME
  • About
    • About the Journals
    • Contact Us
    • Editorial Board
  • Authors
    • Submit New Manuscript
    • Submit Revised Manuscript
    • Author Center

Advanced Search

Main menu

  • Neurology.org
  • Journals
    • Neurology
    • Clinical Practice
    • Education
    • Genetics
    • Neuroimmunology & Neuroinflammation
  • Online Sections
    • Neurology Video Journal Club
    • Diversity, Equity, & Inclusion (DEI)
    • Neurology: Clinical Practice Accelerator
    • Practice Buzz
    • Practice Current
    • Residents & Fellows
    • Without Borders
  • Collections
    • COVID-19
    • Disputes & Debates
    • Health Disparities
    • Infographics
    • Neurology Future Forecasting Series
    • Null Hypothesis
    • Patient Pages
    • Topics A-Z
    • Translations
    • UDDA Revision Series
  • Podcast
  • CME
  • About
    • About the Journals
    • Contact Us
    • Editorial Board
  • Authors
    • Submit New Manuscript
    • Submit Revised Manuscript
    • Author Center
  • Home
  • Latest Articles
  • Current Issue
  • Past Issues
  • Neurology Video Journal Club
  • Residents & Fellows

User menu

  • Subscribe
  • My Alerts
  • Log in

Search

  • Advanced search
Neurology
Home
The most widely read and highly cited peer-reviewed neurology journal
  • Subscribe
  • My Alerts
  • Log in
Site Logo
  • Home
  • Latest Articles
  • Current Issue
  • Past Issues
  • Neurology Video Journal Club
  • Residents & Fellows

Share

April 09, 2019; 92 (15 Supplement) May 10, 2019

RNAi/gene therapy combined approach as therapeutic strategy for Charcot-Marie-Tooth 2A (S58.005)

Federica Rizzo, Silvia Bono, Sabrina Salani, Andreina Bordoni, Valentina Melzi, Marc Ruepp, Serena Pagliarani, Kordelia Barbullushi, Elena Abati, Chiara Cordiglieri, Nereo Bresolin, Giacomo Comi, Monica Nizzardo, Stefania Corti
First published April 16, 2019,
Federica Rizzo
1University of Milan Milan Italy
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Silvia Bono
2IRCCS Foundation Ca’ Granda Ospedale Maggiore Policlinico Milan Italy
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sabrina Salani
2IRCCS Foundation Ca’ Granda Ospedale Maggiore Policlinico Milan Italy
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Andreina Bordoni
2IRCCS Foundation Ca’ Granda Ospedale Maggiore Policlinico Milan Italy
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Valentina Melzi
2IRCCS Foundation Ca’ Granda Ospedale Maggiore Policlinico Milan Italy
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Marc Ruepp
3King’s College London United Kingdom
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Serena Pagliarani
1University of Milan Milan Italy
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kordelia Barbullushi
1University of Milan Milan Italy
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Elena Abati
1University of Milan Milan Italy
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Chiara Cordiglieri
4Istituto di Genetica Molecolare “Romeo ed Enrica Invernizzi” Milan Italy
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Nereo Bresolin
1University of Milan Milan Italy
2IRCCS Foundation Ca’ Granda Ospedale Maggiore Policlinico Milan Italy
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Giacomo Comi
1University of Milan Milan Italy
2IRCCS Foundation Ca’ Granda Ospedale Maggiore Policlinico Milan Italy
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Monica Nizzardo
1University of Milan Milan Italy
2IRCCS Foundation Ca’ Granda Ospedale Maggiore Policlinico Milan Italy
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Stefania Corti
1University of Milan Milan Italy
2IRCCS Foundation Ca’ Granda Ospedale Maggiore Policlinico Milan Italy
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Citation
RNAi/gene therapy combined approach as therapeutic strategy for Charcot-Marie-Tooth 2A (S58.005)
Federica Rizzo, Silvia Bono, Sabrina Salani, Andreina Bordoni, Valentina Melzi, Marc Ruepp, Serena Pagliarani, Kordelia Barbullushi, Elena Abati, Chiara Cordiglieri, Nereo Bresolin, Giacomo Comi, Monica Nizzardo, Stefania Corti
Neurology Apr 2019, 92 (15 Supplement) S58.005;

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Permissions

Make Comment

See Comments

Downloads
0

Share

  • Article
  • Info & Disclosures
Loading

Abstract

Objective: To investigate a novel therapeutic approach for Charchot-Marie-Tooth disease type 2A (CMT2A) using RNAi/gene therapy combination.

Background: CMT2A is a rare inherited axonal peripheral neuropathy caused by mutations in the mitofusin 2 (MFN2) gene and characterized by progressive distal muscle weakness, atrophy, sensory loss, and normal or near-normal nerve conduction velocities. MFN2 mutations have been characterized and numerous mechanisms proposed to unravel CMT2A pathophysiology; however, no cure for this devastating disease is available. Thus, it is crucial to identify a treatment to cure or at least mitigate CMT2A progression.

Design/Methods: Our proposed approach combined RNA interference (RNAi) with gene therapy as therapeutic strategy for CMT2A. In induced pluripotent stem cells (iPSCs) obtained from CMT2A patients we targeted the MFN2 mutant allele with specific short hairpin RNAs (shRNAs) and simultaneously introduced a mutagenized MFN2 gene able to be resistant to shRNA activity and still encoding the native protein. We then differentiated iPSCs into spinal motor neurons (MNs) and analyzed the sub-cellular parameters we previously found to be altered in CMT2A in vitro model (Rizzo et al., 2016) were evaluated to assess the impact of our therapy.

Results: We successfully silenced endogenous MFN2 gene and restored functional MFN2 protein level in CMT2A cells without altering iPSC pluripotency. In addition, MNs differentiated from both treated and untreated CMT2A iPSCs showed typical MN morphology and expressed the main MN markers. Qualitative and quantitative alterations characteristic of CMT2A disease (Rizzo et al., 2016) were restored after our therapy in CMT2A MNs. Specifically, we observed an increase in mitochondria number, an improvement of mitochondrial axonal transport, re-established sensitivity to apoptosis and reduction of authophagy/mytophagy.

Conclusions: Overall, our results led to a significant level of rescue in CMT2A MNs, suggesting RNAi/gene therapy combined approach as a promising therapeutic strategy for CMT2A.

Disclosure: Dr. Rizzo has nothing to disclose. Dr. Bono has nothing to disclose. Dr. Salani has nothing to disclose. Dr. Bordoni has nothing to disclose. Dr. Melzi has nothing to disclose. Dr. Ruepp has nothing to disclose. Dr. Pagliarani has nothing to disclose. Dr. Barbullushi has nothing to disclose. Dr. Abati has nothing to disclose. Dr. Cordiglieri has nothing to disclose. Dr. Bresolin has nothing to disclose. Dr. Comi has nothing to disclose. Dr. Nizzardo has nothing to disclose. Dr. Corti has nothing to disclose.

Letters: Rapid online correspondence

No comments have been published for this article.
Comment

REQUIREMENTS

You must ensure that your Disclosures have been updated within the previous six months. Please go to our Submission Site to add or update your Disclosure information.

Your co-authors must send a completed Publishing Agreement Form to Neurology Staff (not necessary for the lead/corresponding author as the form below will suffice) before you upload your comment.

If you are responding to a comment that was written about an article you originally authored:
You (and co-authors) do not need to fill out forms or check disclosures as author forms are still valid
and apply to letter.

Submission specifications:

  • Submissions must be < 200 words with < 5 references. Reference 1 must be the article on which you are commenting.
  • Submissions should not have more than 5 authors. (Exception: original author replies can include all original authors of the article)
  • Submit only on articles published within 6 months of issue date.
  • Do not be redundant. Read any comments already posted on the article prior to submission.
  • Submitted comments are subject to editing and editor review prior to posting.

More guidelines and information on Disputes & Debates

Compose Comment

More information about text formats

Plain text

  • No HTML tags allowed.
  • Web page addresses and e-mail addresses turn into links automatically.
  • Lines and paragraphs break automatically.
Author Information
NOTE: The first author must also be the corresponding author of the comment.
First or given name, e.g. 'Peter'.
Your last, or family, name, e.g. 'MacMoody'.
Your email address, e.g. higgs-boson@gmail.com
Your role and/or occupation, e.g. 'Orthopedic Surgeon'.
Your organization or institution (if applicable), e.g. 'Royal Free Hospital'.
Publishing Agreement
NOTE: All authors, besides the first/corresponding author, must complete a separate Publishing Agreement Form and provide via email to the editorial office before comments can be posted.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.

Vertical Tabs

You May Also be Interested in

Back to top
  • Article
  • Info & Disclosures
Advertisement

Association of Mediterranean-DASH Intervention for Neurodegenerative Delay and Mediterranean Diets With Alzheimer Disease Pathology

Dr. Babak Hooshmand and Dr. David Smith

► Watch

Related Articles

  • No related articles found.

Alert Me

  • Alert me when eletters are published
Neurology: 101 (12)

Articles

  • Ahead of Print
  • Current Issue
  • Past Issues
  • Popular Articles
  • Translations

About

  • About the Journals
  • Ethics Policies
  • Editors & Editorial Board
  • Contact Us
  • Advertise

Submit

  • Author Center
  • Submit a Manuscript
  • Information for Reviewers
  • AAN Guidelines
  • Permissions

Subscribers

  • Subscribe
  • Activate a Subscription
  • Sign up for eAlerts
  • RSS Feed
Site Logo
  • Visit neurology Template on Facebook
  • Follow neurology Template on Twitter
  • Visit Neurology on YouTube
  • Neurology
  • Neurology: Clinical Practice
  • Neurology: Education
  • Neurology: Genetics
  • Neurology: Neuroimmunology & Neuroinflammation
  • AAN.com
  • AANnews
  • Continuum
  • Brain & Life
  • Neurology Today

Wolters Kluwer Logo

Neurology | Print ISSN:0028-3878
Online ISSN:1526-632X

© 2023 American Academy of Neurology

  • Privacy Policy
  • Feedback
  • Advertise