# Anti-inflammatory and hMSC combination therapy for traumatic brain injury

> **NIH VA I01** · JAMES A. HALEY VA MEDICAL CENTER · 2023 · —

## Abstract

The long-term goal of our research program is to develop safe and effective therapies for traumatic brain
injury (TBI), which is a major health issue with our military personnel in combat. The prevalence of TBI
from all causes is estimated at ~2.5 to 3.7 million cases in the USA alone. Currently, there are no FDA-
approved drugs available to treat TBI. While TBI illness ranges from mild to severe, moderate TBI is
clinically most relevant, and If not treated immediately the secondary injury in these patients could spread
quickly and may lead to long-term consequences including cognitive and memory loss. Mesenchymal
stem cells (MSCs) transplantation has emerged as one of the major approaches to treat TBI. However,
the viability of sole MSC therapy is being debated due to the uncertainty of variable engraftment in
inflammatory state. Hence, there is a genuine unmet need to discover and develop new therapeutic
agents for all forms of TBI, especially moderate TBI.
 It has been reported that adding an anti-inflammatory agent prior to MSC treatment increased the
latter’s efficacy. During the last funding period, we have established an experimental mouse model to
enable characterization of the consequences of repeated TBI (rTBI) in closed head injury, which shows
extensive neuropathologic changes associated with the cognitive deficit, consistent with human TBI. We
made the striking discovery that the expression of chemokine (C-C motif) ligand 20 (CCL20) (MIP3α)
is pivotal to inflammation in TBI, implicating CCL20 as a potential TBI drug target. We have
demonstrated that CCL20 inhibitor, pioglitazone (PG), played a key role in reducing astrogliosis,
microglial activation and inflammasome activation in TBI. A combination of PG and hMSC treatment
not only reduced inflammation but also improved behavioral outcomes by increasing the expression
of brain-derived neurotrophic factor (BDNF). Because PG is not a specific CCL20 inhibitor and may
have off-target effects, we have established and validated a nanoformulation of short hairpin RNA
(shRNA) plasmids encoding CCL20 and its receptor CCR6 using dendrimer. A combination treatment
involving shCCL20/shCCR6 (shCombo) and human MSC (hMSC) showed a significant reduction in
inflammation, a concomitant increase in BDNF and neurogenesis in rTBI mouse model.
 Based on our preliminary data, we hypothesize that the shCombo dendriplex (DPX) or/and
hMSC combination regimen will attenuate both acute brain- and systemic-inflammation by
decreasing activation of glial cells and astrocytes in the brain, and secreting trophic factors over a
prolonged period, which in turn promotes neuronal remodeling in the damaged brain and provides
sustained relief from TBI-induced pathology. Three specific aims are proposed to test this hypothesis. In
Aim #1, we will determine the optimal dose of pshCombo-DPX and the therapeutic window of treatment
in rTBI mice. In Aim #2 we will examine the short-term and long-term effects of shCombo-DPX or/...

## Key facts

- **NIH application ID:** 10486391
- **Project number:** 1I01BX005757-01A1
- **Recipient organization:** JAMES A. HALEY VA MEDICAL CENTER
- **Principal Investigator:** SUBHRA MOHAPATRA
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2023
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2022-10-01 → 2026-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10486391

## Citation

> US National Institutes of Health, RePORTER application 10486391, Anti-inflammatory and hMSC combination therapy for traumatic brain injury (1I01BX005757-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10486391. Licensed CC0.

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