# Neurobehavioral, cognitive, and mechanistic effects of intranasally administered neural stem cells and environmental enrichment after cortical impact injury in rats

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $494,198

## Abstract

Traumatic brain injury (TBI) affects more than 10 million individuals worldwide each year and results in long-
term motor, cognitive, and affective deficits. Pharmacologic strategies are often used to treat TBI but to date no
therapy has successfully translated to the clinic, which advocates for other rehabilitative strategies to restore
neuronal networks and recover behavioral deficits thereby increasing the probability of bench-to-bedside
success. Neural stem cell (NSC) therapies may be a feasible alternative to pharmacotherapies for improving
function after TBI. NSC-based therapies can exploit their inherent ability to migrate to stimulate regeneration
and repair damaged brain tissue. In our pilot studies, well-characterized allogeneic human NSCs, LM-NSC008,
genetically modified to express the human L-Myc gene were intranasally (IN) administered to adult male and
female rats after cortical impact injury. LM-NSC008 cells migrated toward and distributed throughout damaged
brain tissue and into distant regions mediating behavioral changes. LM-NSC008 cells significantly improved
two distinct cognitive domains - spatial learning (reference learning) and executive function vs. vehicle (VEH).
Because clinical translation has been unsuccessful with single therapies, the NIH’s TBI and combination
therapy workshop recommended the evaluation of combination treatments. We have reported synergistic
benefits when environmental enrichment (EE) is combined with pharmacotherapies and predict augmented
benefits with LM-NSC008 cells as well. Our hypotheses are that IN LM-NSC008 cells in male and female rats
will 1) migrate and accumulate in sufficient quantities at proximal and distal TBI sites and contribute to
behavioral recovery, 2) provide benefit with a clinically relevant delayed administration approach, and 3)
improve recovery more robustly when combined with EE than when administered alone. To test our
hypotheses, optimize IN delivery doses of LM-NSC008 cells, and to determine LM-NSC008 cell fate and
mechanisms, alone and in combination with EE, the following Aims are proposed. Aim 1a: Determine the
optimal dose and delivery protocol of IN LM-NSC008 cells for maximal distribution to areas of damage at early,
delayed, and chronic time points after TBI. A single high dose of LM-NSC008 cells [6x106] or VEH will be given
IN on day-7 (acute period), day-21 (delayed), or day-90 (chronic) after moderate TBI or sham injury, while six
lower doses [1x106] will be given once on post-surgery days 7,9,11,13,15,17 (acute), 21,23,25,27,29,31
(delayed), or 90,92,94,96,98,100 (chronic) to determine the protocol that provides maximal distribution of cells
at the trauma sites at 3 timepoints after TBI and significantly improves recovery. Aim 1b: Evaluate motor,
cognitive, and affective behavioral improvements with IN LM-NSC008 cell therapy in TBI and sham rats. Aim 2:
Determine the effect of combining IN LM-NSC008 cell therapy with EE on motor, cognitive, and affective
beh...

## Key facts

- **NIH application ID:** 10914829
- **Project number:** 5R01NS121037-04
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** MARGARITA GUTOVA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $494,198
- **Award type:** 5
- **Project period:** 2021-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10914829

## Citation

> US National Institutes of Health, RePORTER application 10914829, Neurobehavioral, cognitive, and mechanistic effects of intranasally administered neural stem cells and environmental enrichment after cortical impact injury in rats (5R01NS121037-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10914829. Licensed CC0.

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