Precision Gene Therapy for Diseases Driven by Endothelial Dysfunction

SHORT DESCRIPTION
Dual promoter system constructs for tissue-specific and cell-type-specific gene expression, enabling precision gene therapy targeting endothelial dysfunction in specific organs.

• Youyang Zhao*
  • Ann & Robert H Lurie Children's Hospital of Chicago

NU Tech ID  LU 2023-049

IP STATUS
U.S. Patent Pending (U.S. 19/167,785)

DEVELOPMENT STAGE
TRL-5 Prototype Validated in Relevant Environment: Demonstrated vascular repair and inflammation resolution in an aged mouse model.

BACKGROUND
Endothelial cells (ECs) exhibit structural, phenotypic, and functional heterogeneity across different tissues, and tissue-specific EC dysfunction is implicated in major diseases such as atherosclerosis, hypertension, sepsis, and several forms of lung vascular injury. Treatments for these conditions usually address downstream consequences rather than repairing the dysfunctional endothelial compartment itself. Moreover, targeting the endothelial compartment presents challenges since organ-specific endothelial genes are typically expressed in multiple cell types to varying degrees. Selective targeting of tissue-specific ECs while minimizing off-target effects represents a critical unmet need for precision gene therapy.

ABSTRACT
This invention discloses dual or triple promoter systems combining cell-type specific promoters with organ-specific promoters to drive therapeutic gene expression exclusively in target organ ECs. The constructs utilize DNA recombinase systems where the first promoter drives recombinase expression and the second promoter controls the therapeutic gene separated by a recombinase-excisable STOP cassette. Exemplary lung-EC-specific constructs comprise CDH5-Dre-TMEM100-Rox-STOP-Rox-FOXM1, achieving lung-exclusive endothelial expression. In aged mice, this system restored FoxM1 expression, promoted endothelial regeneration, and resolved inflammatory lung injury 72h post-LPS challenge. The technology generalizes to other organs with tissue-specific EC promoters, including heart, aorta, skeletal muscle, brain, liver, and kidney.

APPLICATIONS

• Precision treatment of ARDS, sepsis, and lung inflammatory diseases: Lung EC-specific FOXM1 gene therapy using CDH5-TMEM100 dual promoter systems to restore endothelial barrier function and promote vascular repair.
• Organ-specific vascular disease gene therapy: For other diseases in which endothelial dysfunction is a root driver.
• Tumor-specific anti-angiogenic gene therapy: Delivering anti-angiogenic or pro-apoptotic genes selectively to tumor vasculature.
• Disease-state-specific interventions: Combining inflammatory response promoters with EC promoters to achieve therapeutic gene expression only in activated endothelium during acute inflammatory conditions.
• Research and translational tools to study endothelial biology, validate targets, and compare gene function across vascular beds.

ADVANTAGES

• Unprecedented cell-type and organ-dual specificity: Dual promoter-recombinase gating eliminates off-target expression.
• Enhances vascular repair: Reactivates endothelial regeneration and promotes inflammation resolution.
• Modular, generalizable platform with extensive organ coverage: Provides validated promoter combinations for 14+ organs and 3 recombinase systems.
• Clinical translation-ready delivery with established safety: Utilizes lipid nanoparticle platforms for non-viral systemic delivery.

PUBLICATIONS

• Zhang X et al., Robust genome editing in adult vascular endothelium by nanoparticle delivery of CRISPR-Cas9 plasmid DNA. Cell Rep. 2022 Jan 4.
• Huang et al., Endothelial FoxM1 reactivates aging-impaired endothelial regeneration for vascular repair and resolution of inflammatory lung injury. Sci Transl Med. 2023 Aug 16.

CATEGORY/INDUSTRY PIPELINE
Therapeutics; Biomarkers & Biomedical Research Tools

KEYWORDS
Gene therapy, endothelial dysfunction, dual promoter system, vascular repair, inflammation resolution, precision medicine, targeted gene expression, vascular endothelium, regenerative medicine