Self-inactivating lentiviral vector comprising a FoxP3 expression cassette
Inventors
Kohn, Donald B. • Roncarolo, Maria Grazia • Hollis, Roger Paul • Masiuk, Katelyn E. • Bacchetta, Rosa
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Assignees
University of California, San Diego • Leland Stanford Junior University
MemberStanford UniversityStanford UniversityTodd Coleman is an associate professor of bioengineering at Stanford University. His research combines applied probability, physiology, and bioelectronics to develop methods and devices for monitoring and modulating nervous-system and other physiological activity, including brain and visceral-organ signals.
Todd Coleman is an associate professor of bioengineering at Stanford University. His research combines applied probability, physiology, and bioelectronics to develop methods and devices for monitoring and modulating nervous-system and other physiological activity, including brain and visceral-organ signals.
Publication Number
US-12747454-B2
Publication Date
2026-09-29
Expiration Date
Abstract
In various embodiments, lentiviral vectors expressing FoxP3 using the endogenous gene elements to regulate physiologic gene expression of FoxP3 are provided herein as well as uses of such vectors.
Core Innovation
The invention provides a recombinant HIV-derived, TAT-independent, self-inactivating lentiviral vector comprising human FoxP3-CNS1, human FoxP3-CNS2, and human FoxP3-CNS3 enhancer sequences upstream of a human FoxP3 promoter. A nucleic acid encoding a protein is operably linked to the enhancer elements and promoter to direct lineage-appropriate FoxP3 expression in regulatory T cells. The vector further comprises lentiviral vector elements including a U3 region lacking a TATA box, an R region, a U5 region, a packaging signal, an RRE, and a cPPT.
Reported assays demonstrate lineage-directed expression, showing strong reporter expression in Treg-like MT-2 cells, minimal expression in Jurkat or K562 cells, and enriched in vivo expression in FoxP3+ regulatory T cells. Described studies also report functional restoration of FoxP3-deficient scurfy hematopoietic stem cells, rescue of scurfy disease, Treg-associated phenotypes, and reduced disease-related measures in transplantation and humanized mouse models.
Claims Coverage
The claim coverage includes four inventive features derived from one independent claim and associated dependent claims.
Human FoxP3 enhancer and promoter expression cassette
The independent claim covers an expression cassette comprising human FoxP3-CNS1, FoxP3-CNS2, and FoxP3-CNS3 enhancer sequences located upstream of a human FoxP3 promoter, operably linked to a nucleic acid sequence encoding a protein.
Self-inactivating lentiviral vector architecture
The vector is an HIV-derived, TAT-independent, and self-inactivating lentiviral vector comprising a U3 region lacking a TATA box, an R region, a U5 region, a packaging signal, an RRE, and a cPPT.
Vector length, FoxP3 3′UTR, and lineage-specific expression
The claim elements specify a vector length of less than 10 kb, inclusion of a FoxP3 3′UTR, and enhancer elements configured to drive Treg-lineage-specific expression in cells transfected with the vector.
Packaging cells and pseudotyped lentiviral particles
The claim elements recite packaging cells and infectious lentiviral particles, including particles comprising a heterologous envelope pseudotyped with a VSV-G envelope. [procedural detail omitted for safety]
The independent claim centers on a recombinant lentiviral vector linking a protein-encoding nucleic acid to a human FoxP3 enhancer-promoter cassette, while dependent claims further define structural refinements including vector length, 3′UTR sequences, Treg-specific expression, packaging cells, and pseudotyped particles.
Stated Advantages
The vector provides lineage-directed and Treg-restricted expression, demonstrated by strong reporter expression in Treg-like MT-2 cells, little expression in Jurkat or K562 cells, and enriched in vivo expression in FoxP3+ regulatory T cells.
Treatment with the FoxP3 vector produces Treg-associated phenotypes and reduced disease-related measures in transplant models.
Reported studies describe functional restoration of regulatory T cells from FoxP3-deficient scurfy hematopoietic stem cells and rescue of scurfy disease following transfer of corrected cells.
Documented Applications
Autologous hematopoietic stem/progenitor-cell gene therapy for FoxP3 deficiency, including IPEX syndrome and other autoimmune disorders.
Transplantation models to promote Treg-associated phenotypes, reduce disease-related measures, and evaluate therapies in humanized NSG mouse models.
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