Skip to main content
Advertisement
  • Neurology.org
  • Journals
    • Neurology
    • Clinical Practice
    • Genetics
    • Neuroimmunology & Neuroinflammation
  • Specialty Sites
    • COVID-19
    • Practice Current
    • Practice Buzz
    • Without Borders
    • Equity, Diversity and Inclusion
    • Innovations in Care Delivery
  • Collections
    • Topics A-Z
    • Residents & Fellows
    • Infographics
    • Patient Pages
    • Null Hypothesis
    • Translations
  • Podcast
  • CME
  • About
    • About the Journals
    • Contact Us
    • Editorial Board
  • Authors
    • Submit a Manuscript
    • Author Center

Advanced Search

Main menu

  • Neurology.org
  • Journals
    • Neurology
    • Clinical Practice
    • Genetics
    • Neuroimmunology & Neuroinflammation
  • Specialty Sites
    • COVID-19
    • Practice Current
    • Practice Buzz
    • Without Borders
    • Equity, Diversity and Inclusion
    • Innovations in Care Delivery
  • Collections
    • Topics A-Z
    • Residents & Fellows
    • Infographics
    • Patient Pages
    • Null Hypothesis
    • Translations
  • Podcast
  • CME
  • About
    • About the Journals
    • Contact Us
    • Editorial Board
  • Authors
    • Submit a Manuscript
    • Author Center
  • Home
  • Latest Articles
  • Current Issue
  • Past Issues
  • 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
  • Residents & Fellows

Share

April 14, 2020; 94 (15 Supplement) Sunday, April 26

Thymidine Phosphorylase Intracellular Enzyme Replacement Therapy in a Murine Model of Mitochondrial Neurogastrointestinal Encephalopathy (MNGIE) (3975)

Jonathan Shintaku, Wenlong Lian, Xiang Li, Saba Tadesse, May Theng Ting, Xingfu Xu, Nicholas E. Long, Josell Ramirez-Paz, Ziqing Qian, Natarajan Sethuraman, Michio Hirano
First published April 14, 2020,
Jonathan Shintaku
1Department of Neurology, Columbia University Irving Medical Center
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Wenlong Lian
2Entrada Therapeutics
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Xiang Li
2Entrada Therapeutics
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Saba Tadesse
1Department of Neurology, Columbia University Irving Medical Center
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
May Theng Ting
1Department of Neurology, Columbia University Irving Medical Center
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Xingfu Xu
2Entrada Therapeutics
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Nicholas E. Long
2Entrada Therapeutics
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Josell Ramirez-Paz
2Entrada Therapeutics
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ziqing Qian
2Entrada Therapeutics
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Natarajan Sethuraman
2Entrada Therapeutics
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Michio Hirano
1Department of Neurology, Columbia University Irving Medical Center
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Citation
Thymidine Phosphorylase Intracellular Enzyme Replacement Therapy in a Murine Model of Mitochondrial Neurogastrointestinal Encephalopathy (MNGIE) (3975)
Jonathan Shintaku, Wenlong Lian, Xiang Li, Saba Tadesse, May Theng Ting, Xingfu Xu, Nicholas E. Long, Josell Ramirez-Paz, Ziqing Qian, Natarajan Sethuraman, Michio Hirano
Neurology Apr 2020, 94 (15 Supplement) 3975;

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 assess the efficacy of thymidine phosphorylase (TP) intracellular enzyme replacement therapy (ERT) in experimental models of TP enzyme deficiency.

Background: MNGIE is a slowly progressive, rare autosomal recessive disease caused by mutations in TYMP, which encodes TP. Patients manifest a combination of gastrointestinal dysmotility, severe cachexia, extraocular muscle weakness, peripheral neuropathy, and leukoencephalopathy. MNGIE is characterized by elevated concentrations of the TP substrates thymidine (Thd) and deoxyuridine (dUrd). Elevated Thd/dUrd result in imbalanced deoxynucleoside triphosphate pools which, in turn, cause mitochondrial DNA instability and depletion, and ultimately the MNGIE phenotype. Since current experimental interventions result in excess morbidity and mortality, there is a need for improved therapeutic options for MNGIE patients.

Design/Methods: We developed a series of novel intracellular ERTs consisting of 3 covalently-linked components: 1) an engineered form of recombinant human TP, 2) a cell-penetrating peptide (CPP) to facilitate enzyme delivery into the cell, and 3) a polyethylene glycol chain to optimize the pharmacokinetic properties of the molecules. The activities of multiple TP-ERT constructs were evaluated in 1) a TP-deficient mammalian cell line and 2) the MNGIE murine Tymp−/−Upp1−/− model, in which plasma Thd levels exceed 10 μM, in contrast to 1.5 μM in wild type (WT) mice.

Results: CPP-TP conjugates delivered active TP into TP-deficient cells in vitro in a dose-dependent manner. In the MNGIE Tymp−/−Upp1−/− mouse model, the lead CPP-TP construct, ENTR-501, rapidly reduced plasma Thd/dUrd to WT or lower levels that were sustained for 72 hours after a single dose of 5 mg/kg. Reduced Thd/dUrd levels were repeatedly achieved following weekly doses of 5 mg/kg ENTR-501.

Conclusions: CPP-conjugated-TP corrected metabolic abnormalities in the TP-deficient MNGIE mouse. These data support the development of CPP-TP intracellular enzyme replacement therapy for MNGIE.

Disclosure: Dr. Shintaku has received research support from Entrada Therapeutics.Dr. Lian has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Entrada Therapeutics. Dr. Li has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Entrada Therapeutics. Dr. Tadesse has received research support from Entrada Therapeutics. Dr. Ting has received research support from Entrada Therapeutics. Dr. Xu has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Entrada Therapeutics. Dr. Long has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Entrada Therapeutics. Dr. Ramirez-Paz has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Entrada Therapeutics. Dr. Qian has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Entrada Therapeutics. Dr. Qian holds stock and/or stock options in Entrada Therapeutics which sponsored research in which Dr. Qian was involved as an investigator. Dr. Sethuraman has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Entrada Therapeutics. Dr. Sethuraman holds stock and/or stock options in Entrada Therapeutics which sponsored research in which Dr. Sethuraman was involved as an investigator. Dr. Hirano has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Modis Therapeutics, and Entrada Therapeutics. Dr. Hirano has received research support from Entrada Therapeutics, and Stealth Biotherapeutics.

Disputes & Debates: Rapid online correspondence

No comments have been published for this article.
Comment

NOTE: All authors' disclosures must be entered and current in our database before comments can be posted. Enter and update disclosures at http://submit.neurology.org. Exception: replies to comments concerning an article you originally authored do not require updated disclosures.

  • Stay timely. Submit only on articles published within the last 8 weeks.
  • Do not be redundant. Read any comments already posted on the article prior to submission.
  • 200 words maximum.
  • 5 references maximum. Reference 1 must be the article on which you are commenting.
  • 5 authors maximum. Exception: replies can include all original authors of the article.
  • 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 Disputes & Debates Submission 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

Related Articles

  • No related articles found.

Alert Me

  • Alert me when eletters are published
Neurology: 96 (2)

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: Genetics
  • Neurology: Neuroimmunology & Neuroinflammation
  • AAN.com
  • AANnews
  • Continuum
  • Brain & Life
  • Neurology Today

Wolters Kluwer Logo

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

© 2021 American Academy of Neurology

  • Privacy Policy
  • Feedback
  • Advertise