Development of a DIPG Orthotopic Model in Mice Using an Implantable Guide-Screw System

Abstract

ObjectiveIn this work we set to develop and to validate a new in vivo frameless orthotopic Diffuse Intrinsic Pontine Glioma (DIPG) model based in the implantation of a guide-screw system.MethodsIt consisted of a guide-screw also called bolt, a Hamilton syringe with a 26-gauge needle and an insulin-like 15-gauge needle. The guide screw is 2.6 mm in length and harbors a 0.5 mm central hole which accepts the needle of the Hamilton syringe avoiding a theoretical displacement during insertion. The guide-screw is fixed on the mouse skull according to the coordinates: 1mm right to and 0.8 mm posterior to lambda. To reach the pons the Hamilton syringe is adjusted to a 6.5 mm depth using a cuff that serves as a stopper. This system allows delivering not only cells but also any kind of intratumoral chemotherapy, antibodies or gene/viral therapies.ResultsThe guide-screw was successfully implanted in 10 immunodeficient mice and the animals were inoculated with DIPG human cell lines during the same anesthetic period. All the mice developed severe neurologic symptoms and had a median overall survival of 95 days ranging the time of death from 81 to 116 days. Histopathological analysis confirmed tumor into the pons in all animals confirming the validity of this model.ConclusionHere we presented a reproducible and frameless DIPG model that allows for rapid evaluation of tumorigenicity and efficacy of chemotherapeutic or gene therapy products delivered intratumorally to the pons.

DNX-2401, an Oncolytic Virus, for the Treatment of Newly Diagnosed Diffuse Intrinsic Pontine Gliomas: A Case Report

“…This information has the potential to alter the diagnostic perspective and treatment options to achieve the best patient outcome. Furthermore, tissue analysis will aid the development of reliable transgenic animal models of DIPG ( 20 ).…”

Diffuse Intrinsic Pontine Glioma : Clinical Features, Molecular Genetics, and Novel Targeted Therapeutics

“…In terms of xenograft material delivery, there have also been developments on the technical side of preclinical models in DIPG. A recent publication replaced the stereotactic frame traditionally used to deliver cells into CDOX and PDOX models with a guide-screw bolt [ 36 ]. The main advantage of this technique is the ability to leave the bolt in place and use it as a conduit for delivery of intratumoural chemotherapy, antibodies, and gene or viral therapies.…”

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“…Models using in utero electroporation to deliver PiggyBac DNA transposon plasmids expressing H3.3 K27M in neural progenitor cells have also been developed [22,23]. Marigil et al recently developed a guide-screw system based DIPG xenograft model, which allows the generation of tumors in a fast and reproducible fashion and allows to deliver the therapeutics via the same screw fixed system route [6,24,25]. Smith et al recently performed a comprehensive histopathological and molecular analysis of 37 novel patient-derived orthotopic xenograft (PDOX) models developed from pediatric brain tumor patients [26], associated datasets can be accessed at (http://pbtp.stjude.cloud).…”