# Modeling IDH Mutant Gliomas by Genetic Engineering of Brain Organoid

> **NIH VA I01** · BIRMINGHAM VA MEDICAL CENTER · 2024 · —

## Abstract

Project Summary/Abstract
Gliomas are incurable and are the number two cause for tumor mortality in adult under 40 years old.
Monoallelic mutations of IDH1 and IDH2, which encode isocitrate dehydrogenases (IDH) that convert
isocitrate into α-ketoglutarate (αKG), have been detected in 80% of low grade gliomas (LGG) and nearly
all secondary glioblastoma multiform (GBM). However, because IDH mutation-bearing glioma cells are
difficult to isolate and propagate, an experimental system that allows dissection of the roles of IDH
mutations and the subsequent genetic events in gliomagenesis is currently unavailable. Our overall goal
is to understand the molecular mechanism underlying gliomagenesis and to identify novel targets to
treat gliomas. It is generally believed that gliomas are originated from brain progenitor cells such as
neural progenitor cells (NPCs). However, these cells are inaccessible for experimentation. Human
pluripotent stem cells (hPSCs), such as human embryonic stem cells and induced pluripotent stem cells
(iPSCs), have the potential to differentiate into different somatic cell types and organoids including
brain organoid. Brain organoids possess primitive brain structure with different cell types and therefore
may provide a microenvironment permissive for gliomagenesis. We hypothesize that iPSCs derived
brain organoids serve as an alternative source for human brain cells, which can be used to dissect the
roles of IDH mutations and other associated genetic events in LGGs. The objective of this proposal is
to establish a novel brain organoid model for LGGs allowing assess the roles of IDH1 mutations and
other glioma-associated genetic alterations in disease-relevant cell types. The rationale is that by
establishing such a LGG model, we will be able to dissect the underlying molecular mechanism of
gliomagenesis. These discoveries will ultimately facilitate identification of novel therapeutic targets and
strengthen our capacity for therapeutic intervention. To achieve the objective, three specific aims are
proposed. In Aim 1, we will assess the roles of IDH and TP53 mutations in gliomagenesis using the
brain organoid LGG model. We will first generate brain organoid from iPSCs and then introduce
genetic changes including IDH1 mutation and TP53 knock-down. In Aim 2, we will assess the role of
ATRX mutation in brain organoid based gliomagenesis in vitro. In Aim 3. We will characterize brain
organoid-derived xenograft tumor in comparison to genetically engineered brain organoids and patient
LGGs. If successfully completed, we expect to establish a novel brain organoid model for LGGs, which
will enable us to assess the specific roles of IDH mutations and other glioma-associated genetic
mutations in tumorigenesis. The project will ultimately facilitate identification of novel drug targets
and development of new therapies to treat gliomas.

## Key facts

- **NIH application ID:** 10701326
- **Project number:** 1I01BX006107-01A1
- **Recipient organization:** BIRMINGHAM VA MEDICAL CENTER
- **Principal Investigator:** Xiaosi Han
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2023-10-01 → 2027-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10701326

## Citation

> US National Institutes of Health, RePORTER application 10701326, Modeling IDH Mutant Gliomas by Genetic Engineering of Brain Organoid (1I01BX006107-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10701326. Licensed CC0.

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