# Evaluation of immune responses to CD44-targeted nanovectors for designing a novel anti-tuberculosis host-directed therapy

> **NIH NIH R21** · METHODIST HOSPITAL RESEARCH INSTITUTE · 2020 · $258,925

## Abstract

ABSTRACT
 Innovative treatment approaches are desperately needed for the 10.4 million new cases/year of
Tuberculosis (TB). Up to 20% of these patients fail to complete antibiotic treatment, as it requires at least 6
months of multiple drugs with significant side effects. Incomplete treatment leads to disease with multi-drug
resistant strains. Manipulating the host immune response to Mycobacterium tuberculosis (Mtb) represents an
attractive alternative to antibiotics as only 5-10% of subjects with evidence of an immune response to TB will
develop active TB disease. Yet, such efforts are stalled because Mtb sets up chronic infection within innate
immune cells in the lung through manipulating their activation state and microbial killing pathways. Altered innate
cell function delays arrival of activated T lymphocytes to the lung resulting in impaired Mtb killing. In this
exploratory proposal, we propose to test a novel host-directed therapeutic (HDT) strategy for active TB. We do
this via inhaled nanoparticles to mimic the effects of an immune danger signal targeted specifically toward Mtb-
infected macrophages.
 In our preliminary studies, we found that Mtb infected macrophages increase their surface expression of
the hyaluronic acid (HA) receptor CD44. Low molecular weight hyaluronan (LMWHA) acts as an endogenous
danger signal and induces classical macrophage activation through its receptor CD44. Furthermore, it induces
macrophages to secrete specific cytokines/chemokines, which facilitate T cell migration to the site of infection.
In our initial studies, we conjugated silicone mesoporous nanovectors (SMP), with CD44-specific Thioaptamers
(CD44TA) targeting CD44 (CD44TA-SMP). A single injection into Mtb infected mice caused greater than a log
decrease in Mtb load. This was associated with selective entry of CD44TA-SMP into Mtb infected macrophages
and induction of macrophage mediated Mtb killing. CD44TA-SMP treatment did not cause toxicities in uninfected
cells and tissues.
 In response to reviewers' critiques, to achieve feasibility of use in point of care settings/ scale up needs,
we propose using CD44TA conjugated to biocompatible and biodegradable phospholipid-based liposomes
(CD44TA-LIP) via nebulized aerosol delivery given with or without anti-Mtb drugs. In this exploratory proposal,
we want to determine the safety and efficacy of CD44TA-LIP in Mtb infected mice. Additionally, we expect to
determine if CD44TA-LIP treatment induces LMWHA-specific immune responses outlined above to overcome
Mtb infection. Specific Aims of this project are 1: To determine optimal dosage, biodistribution, efficacy and safety
of inhaled CD44TA-LIP. 2: To assess the nature of the immune responses generated by short and long-term
inhaled CD44TA-LIP on innate and adaptive cellular immunity against Mtb. Understanding how CD44TA-LIP
enhance host immunity against the pathogen will be critical to using it as host-directed therapy in future large
animal and phase I human ...

## Key facts

- **NIH application ID:** 10142214
- **Project number:** 7R21AI137533-02
- **Recipient organization:** METHODIST HOSPITAL RESEARCH INSTITUTE
- **Principal Investigator:** Biana Godin
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $258,925
- **Award type:** 7
- **Project period:** 2019-05-14 → 2022-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10142214

## Citation

> US National Institutes of Health, RePORTER application 10142214, Evaluation of immune responses to CD44-targeted nanovectors for designing a novel anti-tuberculosis host-directed therapy (7R21AI137533-02). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10142214. Licensed CC0.

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