# Microparticle Therapy for Cerebral Amyloid Angiopathy

> **NIH NIH R44** · KARAMEDICA, INC. · 2021 · $1,119,539

## Abstract

PROJECT SUMMARY
Cerebral Amyloid Angiopathy (CAA), a microvasculopathy in which beta-amyloid (Aβ) accumulates in the walls
of cerebral blood vessels, is associated with vascular fragility and bleeding secondary to blood vessel wall
breakdown. CAA is especially deleterious to vascular smooth muscle cells (VSMC). CAA is found in 70-90% of
Alzheimer's disease (AD) cases, increases hemorrhagic stroke risk, and is exacerbated by active amyloid
immunotherapy thereby compromising this promising AD therapeutic. There is no effective therapy for CAA.
Despite the prevalence of CAA in AD and the fact that AD and CAA are different diseases, CAA is often
overlooked in AD studies as Aβ has been widely presumed to be responsible for the VSMC loss in the walls of
Aβ-laden vessels. VSMC loss in CAA occurs due to formation of the complement system's cytolytic membrane
attack complex (MAC) in the tunica media of Aβ-laden CAA blood vessels. Based on this discovery by our
scientific team, our goal is to develop a first-ever therapeutic for CAA based on inhibition of MAC formation which
we hypothesize will prevent CAA-induced vascular fragility. We plan to target inhibition of MAC formation in the
walls of Aβ-laden CAA blood vessels, as opposed to systemic MAC inhibition, due to the importance of MAC for
immune protection against microbial infection. We propose a nose-to-brain nanoparticle therapy made of
depyrogenated chitosan modified with diethylethylamine (DEAE) that delivers an encapsulated CD59 plasmid
whose expression abrogates the formation of MAC. We have developed a technique to depyrogenate chitosan
that enables internal placement since commercially available chitosans are contaminated with endotoxins. These
contaminants interfere with plasmid transfection and gene expression. Our chitosan depyrogenation technique
is based on the application of nitrogen plasma – the same technology employed to decontaminate potential
anthrax letters sent to Congress after 9/11. We completed a Phase I SBIR in which we established successful
transfection of primary human VSMCs with chitosan gene-containing nanoparticles, induced surface expression
of CD59 in VSMCs via nanoparticle transfection, and established successful protection of CD59 transfected cells
from MAC-initiated cell lysis. In this Phase II SBIR, we intend to (1) improve production of uniform, reproducible
DEAE chitosan nanoparticles that are stable over time so as to achieve consistent, predictable in vivo
transfection of brain microvasculature and provide parenchymal protection, (2) characterize the therapeutic
efficacy of our nose-to-brain CS-CD59 nanoparticle CAA therapy in a relevant transgenic mouse model of CAA,
and (3) determine histologic, physiologic, and cognitive effects in the transgenic CAA mouse model of enhanced
CD59 expression. Successful completion of this project will help enable informed translation of our DEAE
chitosan nanoparticle therapy for CAA into the clinic.

## Key facts

- **NIH application ID:** 10266159
- **Project number:** 5R44AG059478-04
- **Recipient organization:** KARAMEDICA, INC.
- **Principal Investigator:** WOLFF M. KIRSCH
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,119,539
- **Award type:** 5
- **Project period:** 2018-05-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10266159

## Citation

> US National Institutes of Health, RePORTER application 10266159, Microparticle Therapy for Cerebral Amyloid Angiopathy (5R44AG059478-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10266159. Licensed CC0.

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