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Oxidation-resistant Anti-protease Therapy

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 4R42HL140670-02
Agency Tracking Number: R42HL140670
Amount: $1,499,103.00
Phase: Phase II
Program: STTR
Solicitation Topic Code: NHLBI
Solicitation Number: PA16-303
Timeline
Solicitation Year: 2016
Award Year: 2019
Award Start Date (Proposal Award Date): 2019-06-01
Award End Date (Contract End Date): 2021-05-31
Small Business Information
106 W 117TH ST
New York, NY 10026-2256
United States
DUNS: 080561393
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 RONALD CRYSTAL
 (646) 962-4363
 rgcryst@med.cornell.edu
Business Contact
 RONALD CRYSTAL
Phone: (212) 746-2258
Email: rgcryst@med.cornell.edu
Research Institution
 WEILL MEDICAL COLL OF CORNELL UNIV
 
1300 YORK AVENUE, BOX 89
NEW YORK, NY 10065-4805
United States

 Nonprofit college or university
Abstract

Abstract. LEXEO Therapeutics, LLC, is an early stage biotechnology company focused on using gene
therapy technologies to protect vulnerable organs from oxidant stress. LEX01, the 1st LEXEO product, is a
1st in class, next generation gene therapy treatment for alpha 1-antitrypsin (AAT) deficiency, an autosomal
recessive hereditary disorder associated with low serum levels of AAT. AAT (SERPINA1), a 52 kDa serine
antiprotease produced by the liver, protects the lung from proteolytic enzymes released by inflammatory
cells. In AAT deficiency, the lung is vulnerable to destruction by proteolytic enzymes released by inflammatory
cells that degrade the lung, resulting in emphysema. AAT deficiency is currently treated with
weekly infusions of AAT purified from pooled human plasma. Gene therapy for AAT deficiency holds the
promise that a single administration will generate sufficient amounts of AAT to protect the lung on a persistent
basis, obviating weekly AAT protein therapy. First generation gene therapy strategies are under development
to treat AAT deficiency using adenoassociated virus (AAV) gene transfer vectors to deliver the
human AAT coding sequence in vivo by various routes. The Achilles heel of these strategies is the sensitivity
of the AAT molecule to oxidants. The active site of human AAT includes Met358, with a 2° contribution
by Met351. When oxidized (e.g., by cigarette smoke, inflammatory cell products, ambient pollution),
AAT is rendered ineffective and cannot inhibit neutrophil elastase, its primary target. LEX01, designed as
an AAV vector coding for an elastase-inhibiting, oxidation-resistant human AAT, solves this problem
with substitution at Met358 and/or Met351 with Val or Leu to render the AAT molecule oxidation resistant,
yet maintaining its function as an anti-elastase. This is a Fast Track application with the goal of being
clinical trial-ready within 3 yr. Successful completion of these aims will make LEXEO attractive for
biotech, pharma and/or venture investment. Phase I, Aim 1. Using the normal M1(A213) AAT coding
sequence as a base, assess combinations of Met, Leu and Val at positions 351 and 358 to determine the
optimal neutrophil elastase inhibiting, oxidation resistant form of AAT to use in LEX01. Phase I, Aim 2.
Determine that intrapleural administration of LEX01 to experimental animals results in persistent, high levels
of oxidation-resistant human AAT in serum and lung epithelial lining fluid. Phase I, Aim 3. Have a pre-
IND meeting with the FDA regarding the LEX01 development plan. Phase II, Aim 1. Produce and validate
GMP clinical grade LEX01 and demonstrate in experimental animals it is safe to use in a human trial.
Phase II, Aim 2. Develop and validate the assays to be used in the clinical study. Submit to the FDA an
IND permitting initiation of a phase I clinical study of LEX01 for AAT deficiency.Narrative. LEXEO Therapeutics is developing a 1st in class, next generation, gene therapy strategy to
treat alpha 1-antitrypsin (AAT) deficiency, a hereditary disorder associated with early development of
emphysema. The deliverable of this Fast Track application is an FDA-approved investigational new
drug application permitting initiation of a phase I clinical trial to treat AAT deficiency with a singleadministration of LEX01, an adeno-associated gene transfer vector coding for a non-oxidizable form of
AAT.

* Information listed above is at the time of submission. *

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