# Anti-eosinophil Gene Therapy for Eosinophilic Esophagitis

> **NIH NIH R41** · ENYX THERAPEUTICS, LLC · 2022 · $300,000

## Abstract

Abstract. Eosinophilic esophagitis (EoE), a chronic upper gastrointestinal disabling disorder affecting
children and adults, is characterized by eosinophil esophageal inflammation, progressive disordering of
esophageal architecture, esophageal dysfunction, dysphagia and food impaction. There are no approved
therapies for EoE; standard of care includes topical or systemic glucocorticoids and diet modification.
LEXEO Therapeutics, an early stage gene therapy company, is developing a single administration gene
therapy to treat EoE with LXi02, a nonhuman primate serotype rh.10 adeno-associated virus (AAVrh.10)
vector administered intravenously, designed to genetically modify the liver to express and secrete a
monoclonal antibody directed against eosinophils, resulting in clearance of eosinophils from the circulation
and tissues. The advantage of gene therapy over conventional monoclonal therapy is persistent stable
levels of the anti-Eos monoclonal following single intravenous therapy. In collaboration with the Crystal
laboratory, Weill Cornell, a novel murine EoE model was created, induced by sensitization to peanuts,
resulting in esophageal eosinophil accumulation and concomitant derangement of esophageal
architecture. A single intravenous administration of AAVrh.10mAnti-Eos coding for anti-Siglec-F, a
monoclonal antibody directed against murine eosinophil sialic acid-binding immunoglobulin-like lectin
(Siglec-F), induced murine eosinophil apoptosis, clearance of blood hyper eosinophilia, reduction in
esophageal eosinophil accumulation reduction in esophageal architectural derangement and decrease in
food impaction. As the next step in translating this therapy to humans, we generated LXi02
(AAVrh.10hAnti-Eos), identical to AAVrh.10mAnti-Eos, but with the coding sequence for anti-Siglec-8, an
IgG1 human ortholog of murine Siglec-F. The focus of this phase I STTR, is to demonstrate that LXi02
is effective as an anti-human eosinophil therapy. We will administer LXi02 intravenously to
immunodeficient mice at varying doses and assess over time liver expression and blood levels of anti-
Siglec-8 and that the expressed anti-Siglec-8 will: bind to Siglec-8 and to human eosinophils; mediate
natural killer cell antibody-dependent cytotoxicity and apoptosis of human eosinophils; enhance clearance
of human eosinophils in immunodeficient mice; and demonstrate that LXi02 gene expression can be shut
off if required. With success of this phase I STTR, LEXEO will apply for a phase 2 STTR, with the goal to
translate LXi02 to human therapy for EoE. Aim 1. To demonstrate that LXi02 will mediate in
immunodeficient mice persistent, steady state levels of anti-Siglec-8 that functions effectively to reduce
levels of human eosinophils. Aim 2. To show that administration of GalNAc conjugated siRNA cognate to
a sequence in LXi02 will suppress expression of the anti-Siglec8 antibody coded by LXi02.

## Key facts

- **NIH application ID:** 10481279
- **Project number:** 1R41AI165000-01A1
- **Recipient organization:** ENYX THERAPEUTICS, LLC
- **Principal Investigator:** RONALD G CRYSTAL
- **Activity code:** R41 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $300,000
- **Award type:** 1
- **Project period:** 2022-05-06 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10481279

## Citation

> US National Institutes of Health, RePORTER application 10481279, Anti-eosinophil Gene Therapy for Eosinophilic Esophagitis (1R41AI165000-01A1). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10481279. Licensed CC0.

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