Thymidine Phosphorylase Intracellular Enzyme Replacement Therapy in a Murine Model of Mitochondrial Neurogastrointestinal Encephalopathy (MNGIE) (3975)
Citation Manager Formats
Make Comment
See Comments

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.
Letters: Rapid online correspondence
REQUIREMENTS
If you are uploading a letter concerning an article:
You must have updated your disclosures within six months: http://submit.neurology.org
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.
You May Also be Interested in
Dr. Jeffrey Allen and Dr. Nicholas Purcell
► Watch
Related Articles
- No related articles found.