# Safety of AAV-mediated C1 Esterase Inhibitor Gene Therapy for Hereditary Angioedema

> **NIH NIH R41** · ENYX THERAPEUTICS, LLC · 2024 · $275,737

## Abstract

Abstract. Hereditary angioedema (HAE) is a potentially life-threatening autosomal dominant disorder
characterized by recurrent swelling of cutaneous tissues, gastrointestinal and respiratory tracts. Almost all
cases are caused by deficiency in plasma C1-esterase inhibitor (C1EI, a serine protease inhibitor coded
by SERPING1 which functions to regulate the contact, complement and fibrinolytic systems. The
deficiency of C1EI leads to uncontrolled, spontaneous activation of C1 and consumption of C2 and C4,
resulting in increased levels of bradykinin which promotes vascular leak. Our focus is to restore functional
levels of C1 esterase inhibitor by providing a copy of the human C1EI cDNA by gene therapy. ENYX
Therapeutics, an early-stage biotechnology company, is collaborating with the R. Crystal laboratory at
Weill Cornell to develop adeno-associated (AAV)-mediated gene therapy for HAE. In a murine model of
C1EI deficiency, one-time administration of an AAVrh.10 gene transfer vector expressing human C1EI
(AAVrh.10hC1EI, ENX05) provides sustained C1EI activity levels in plasma, sufficient to prevent
angioedema episodes. AAVrh10.hC1EI-treated mice displayed a marked decrease in dye extravasation in
paws and organs, compared with untreated littermates, i.e., a single treatment with ENX05 has the
potential to provide long-term protection from angioedema attacks. The goal of this phase 1 STTR is the
next step in translation of this therapy to humans: demonstration of the safety of the therapy. As detailed in
the proposal, C1EI deficient mice were corrected with an ENX05 dose of 4x1012 gc/kg, a dose for which
prior studies have shown that the AAVrh.10 capsid should not pose a safety risk. However, there is the
theoretical risk that overexpression of C1EI could evoke dysfunction of the complement system. We will
test this in nonhuman primates. Specific aim 1. To assess the hypothesis that overexpression of
ENYX05 (AAVrh.10hC1EI) will not cause dysfunction of the complement system. We will assess the
complement system (serum CH50, AH50, C3, C4) and other safety parameters in male and female
nonhuman primates (NHP) following high dose (1013 gc/kg) intravenous administration of ENX05 (to
assess ENX05 administration without preexisting anti-AAVrh.10 immunity) and then in the same NHP over
the next 6 wk following a 2nd high dose (1013 gc/kg) intravenous administration of ENX05 (to assess
ENX05 administration in the context of existing anti-AAVrh.10 immunity). Controls will include nonhuman
primates treated with AAVrh.10Null, a vector identical to ENX05 but without the human C1EI coding
sequence. At the end of the study, all major organs will be assessed at the histologic level. With this study,
assuming there is no observed dysfunction in the complement system evoked by ENX05, we will have
eliminated an important theoretical safety issue in the translation of ENX05 to the clinic.

## Key facts

- **NIH application ID:** 10818251
- **Project number:** 1R41AI181097-01
- **Recipient organization:** ENYX THERAPEUTICS, LLC
- **Principal Investigator:** RONALD G CRYSTAL
- **Activity code:** R41 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $275,737
- **Award type:** 1
- **Project period:** 2024-03-15 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10818251

## Citation

> US National Institutes of Health, RePORTER application 10818251, Safety of AAV-mediated C1 Esterase Inhibitor Gene Therapy for Hereditary Angioedema (1R41AI181097-01). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10818251. Licensed CC0.

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