# Development and Validation of a CNS Organoid Model of Temporal Lobe Epilepsy for Drug Discovery

> **NIH NIH R43** · STEM PHARM, INC. · 2024 · $499,953

## Abstract

Project Summary/Abstract
Microglia-induced neuroinflammation (MiN) plays a critical role in many neurological disorders,
contributing to disease progression and symptomology. In Temporal Lobe Epilepsy (TLE),
hippocampal sclerosis (HS) forms a nidus for persistent MiN that is associated with chronic
epileptic seizures. MiN presents a novel therapeutic target and represents a complementary
therapeutic approach to current anti-seizure medications. TLE is the most common form of drug
resistant epilepsy, impacting 200,000 Americans, and resulting in significant morbidity and
mortality. Discovery of compounds active against MiN have been based almost exclusively on
screening in an immortalized murine BV2 cell model stimulated with pathogenic LPS to induce
neuroinflammation. However, this is a poor surrogate for human TLE-related neuroinflammation
and models with greater fidelity to TLE are critically needed for successful translation.
Stem Pharm’s proprietary human stem cell derived neural organoids allow for incorporation of
microglia in a reproducible, 96-well plate format amenable to drug screening applications. We
have demonstrated that microglia incorporated into our organoids demonstrate a gene signature
that strongly correlates with human in vivo microglia, respond appropriately to inflammatory
stimuli, and model features of neuroinflammation related to TLE. While LPS stimulation can
produce a form of MiN in vitro, it is based on pathogen signaling largely through the TLR4
receptor. In contrast, we will stimulate Stem Pharm’s organoids with Damage Associated
Molecular Pattern (DAMP) molecules that interact with a broad set of microglial receptors and cell
signaling pathways. This is expected to produce MiN more closely resembling that found in TLE
and result in a more effective and translatable drug discovery model. Specific Aims will 1) develop
and characterize DAMP cocktails or DAMP-enriched conditioned media (CM) that optimally
stimulate MiN, 2) apply optimized DAMP cocktails/CM that elicit neuroinflammatory responses in
organoids and assess transcriptional changes with comparison to TLE patient data, and 3)
validate the organoid model by evaluating the ability of known anti-inflammatory compounds to
prevent DAMP-induced MiN. Completion of these aims will result in an in vitro DAMP-based model
of MiN with demonstrable relevance to TLE. This will represent a significant advancement in the
ability to evaluate anti-inflammatory activity of candidate therapeutics in a physiologically relevant
model. A Phase 2 proposal will focus on screening drug candidates capable of regulating
microglia activation in TLE and performing preclinical activities.

## Key facts

- **NIH application ID:** 11008599
- **Project number:** 1R43NS139845-01
- **Recipient organization:** STEM PHARM, INC.
- **Principal Investigator:** Connie S Lebakken
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $499,953
- **Award type:** 1
- **Project period:** 2024-09-15 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11008599

## Citation

> US National Institutes of Health, RePORTER application 11008599, Development and Validation of a CNS Organoid Model of Temporal Lobe Epilepsy for Drug Discovery (1R43NS139845-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/11008599. Licensed CC0.

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