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 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 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 5, 2019

Intrathecal AAV9-SOD1-shRNA Administration for Amyotrophic Lateral Sclerosis (S5.003)

Gretchen Thomsen, Shibi B. Likhite, Sarah Corcoran, Allan Kaspar, Kevin D. Foust, Martin Fugere, Lyndsey Braun, Stephanie Solano, Petra Kaufmann, Kathrin C. Meyer, Brian K. Kaspar
First published April 16, 2019,
Gretchen Thomsen
1AveXis, Inc. San Diego CA United States
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Shibi B. Likhite
2Center for Gene Therapy, Research Institute at Nationwide Children’s Hospital Columbus OH United States
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sarah Corcoran
2Center for Gene Therapy, Research Institute at Nationwide Children’s Hospital Columbus OH United States
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Allan Kaspar
1AveXis, Inc. San Diego CA United States
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kevin D. Foust
1AveXis, Inc. San Diego CA United States
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Martin Fugere
1AveXis, Inc. San Diego CA United States
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lyndsey Braun
1AveXis, Inc. San Diego CA United States
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Stephanie Solano
1AveXis, Inc. San Diego CA United States
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Petra Kaufmann
1AveXis, Inc. San Diego CA United States
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kathrin C. Meyer
2Center for Gene Therapy, Research Institute at Nationwide Children’s Hospital Columbus OH United States
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Brian K. Kaspar
1AveXis, Inc. San Diego CA United States
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Citation
Intrathecal AAV9-SOD1-shRNA Administration for Amyotrophic Lateral Sclerosis (S5.003)
Gretchen Thomsen, Shibi B. Likhite, Sarah Corcoran, Allan Kaspar, Kevin D. Foust, Martin Fugere, Lyndsey Braun, Stephanie Solano, Petra Kaufmann, Kathrin C. Meyer, Brian K. Kaspar
Neurology Apr 2019, 92 (15 Supplement) S5.003;

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 develop a first-in-human gene therapy for amyotrophic lateral sclerosis (ALS) using intrathecal AAV9-SOD1-shRNA administration.

Background: ALS is a neurodegenerative disease affecting motor neurons, leading to death within 3–5 years of diagnosis. There is no known cure. Twenty percent of genetically-associated ALS cases are linked to mutations in the superoxide dismutase-1 (SOD1) gene. Previously, AAV9-mediated delivery of a small hairpin RNA (shRNA) targeting human SOD1 resulted in efficient downregulation in mice and non-human primates (NHPs). In ALS mice we achieved significant extension in survival with a single administration of an experimental recombinant vector, AAV9-GFP-shRNA-SOD1, in newborn animals and also at later stages after disease onset. These highly promising results set the stage for developing this approach further towards translation to clinical trials.

Design/Methods: We modified the experimental vector for clinical trials using an expression cassette for the delivery of shRNA against human SOD1 devoid of any foreign transgenes (GFP) but maintaining the same cassette size. This was efficiently packaged into an AAV9 viral capsid, creating a new AAV9-SOD1-shRNA (“AVXS-301” herein) translatable to the clinic. Intracerebroventricular delivery (ICV) of AVXS-301 directly into the cerebrospinal fluid (CSF) was performed in the SOD1G93A ALS mouse model and in NHPs to reduce SOD1 throughout the CNS.

Results: A one-time ICV administration of AVXS-301 lead to significantly improved motor function and prolonged survival in mice overexpressing human mutated SOD1. We tested this strategy in NHP including 3–4 year old cynomolgus macaques and a 10-year old rhesus macaque to facilitate dose extrapolation to human patients. With a single lumbar intrathecal administration we achieved efficient transduction and SOD1 downregulation throughout the entire CNS in these animal models. Importantly, administration of AVXS-301 appeared safe and well tolerated in both mice and NHPs.

Conclusions: Together, these results represent an important advancement towards clinical trials for ALS patients.

Disclosure: Dr. Thomsen has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, a Novartis company. Dr. Thomsen holds stock and/or stock options in AveXis, a Novartis company which sponsored research in which Dr. Thomsen was involved as an investigator. Dr. Thomsen has received research support from AveXis, a Novartis company. Dr. Likhite has nothing to disclose. Dr. Corcoran has nothing to disclose. Dr. Kaspar has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, a Novartis company. Dr. Foust has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of AveXis, a Novartis company. Dr. Fugere has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of AveXis, a Novartis company. Dr. Braun has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, a Novartis company. Dr. Solano has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis. Dr. Kaufmann has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, a Novartis company. Dr. Meyer has received royalty, license fees, or contractual rights payments from Celenex/Amicus. Dr. Meyer has received research support from Sanofi. Dr. Kaspar has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, a Novartis company.

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 Between Fluctuations in Blood Lipid Levels Over Time With Incident Alzheimer Disease and Alzheimer Disease–Related Dementias

Dr. Sevil Yaşar and Dr. Behnam Sabayan

► Watch

Related Articles

  • No related articles found.

Alert Me

  • Alert me when eletters are published
Neurology: 101 (14)

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