# Intranasal gene delivery for Alzheimer’s disease

> **NIH NIH R21** · UNIVERSITY OF MASSACHUSETTS LOWELL · 2021 · $445,124

## Abstract

PROJECT SUMMARY/ABSTRACT
Iron overload disorders, including hereditary hemochromatosis (HH) and transfusional hemoglobinopathies (e.g.
thalassemia, myelodysplastic syndrome, sickle cell anemia), affect tens of millions of people worldwide. Iron
overload is a well-defined risk factor for the development and progression of several metabolic diseases,
including cardiomyopathy, liver cirrhosis, arthritis, diabetes and hypertriglyceridemia. Importantly, increased iron
stores in the brain are closely associated with neurodegenerative diseases (e.g. Alzheimer’s, Parkinson’s and
Huntington’s diseases). Although iron chelators are efficient to remove excess iron from the body, they exhibit
significant toxicities, including gastrointestinal bleeding, agranulocytosis, infection, tachycardia, kidney failure
and liver fibrosis. Moreover, there is no chelator that effectively restores inappropriately high iron in the brain of
patients with neurodegenerative diseases. Hence, there is an unmet need for a new therapeutic strategy by
controlling the transport of iron in the brain. Ferroportin (FPN) is the primary iron transporter responsible for the
export of intracellular iron. Since FPN is also essential for intestinal iron uptake from diet as well as iron release
from the macrophages to recycle the metal for red blood cell production, tissue-specific modulation of FPN can
be an excellent therapeutic target to modify brain iron transport with minimal systemic effects. Gene therapy can
potentially protect against a number of neurodegenerative diseases, including Alzheimer’s, Parkinson’s, and
Huntington’s diseases, by delivering nucleic acid encoding for therapeutic molecules. Conversely, gene silencing
selectively decreases the levels of unwanted molecules, such as oncogenic proteins and pro-inflammatory
cytokines. We have recently demonstrated that intranasal administration of mRNA in nanoparticles significantly
up-regulated protein expression of the reporter genes, such as luciferase and GFP, in the brain. These results
suggested that in vivo gene delivery can be exploited in the area of iron disorders, and further prompted us to
inquire if a direct delivery of FPN transgene to the brain (site of action) via the intranasal route can mobilize brain
iron stores, while avoiding off-target effects. Thus, our hypothesis is that intranasal administration of FPN mRNA
in cationic liposomes (CL) enhances brain FPN expression, increases efflux of iron out of the brain and
ameliorates iron-induced neuronal impairments. The specific aims are focused on 1) developing and validating
FPN transgene/CL to increase brain FPN levels and iron efflux and 2) evaluating the therapeutic efficacy of FPN
transgene/CL using a mouse model of iron-associated Alzheimer’s disease. Overall, this strategy provides a
selective, effective and safe approach for gene therapy in the area of iron-catalyzed neurodegenerative and
other types of neurological disorders.

## Key facts

- **NIH application ID:** 10308277
- **Project number:** 1R21AG074472-01
- **Recipient organization:** UNIVERSITY OF MASSACHUSETTS LOWELL
- **Principal Investigator:** Mansoor M. Amiji
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $445,124
- **Award type:** 1
- **Project period:** 2021-08-15 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10308277

## Citation

> US National Institutes of Health, RePORTER application 10308277, Intranasal gene delivery for Alzheimer’s disease (1R21AG074472-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10308277. Licensed CC0.

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