Targeting the human CCR5 locus as a safe harbor for the expression of therapeutic proteins
Inventors
Gomez-Ospina, Natalia • PORTEUS, Matthew H. • Scharenberg, Samantha Glynne • Amorin, Alvaro
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Assignees
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-12735711-B2
Publication Date
2026-09-15
Expiration Date
Abstract
The present disclosure provides methods and compositions for treating lysosomal storage disorders in subjects, comprising genetically modifying cells from the subjects ex vivo by integrating therapeutic transgenes into the CCR5 locus.
Core Innovation
The invention concerns genetically modifying a cell from a subject with a lysosomal storage disorder to express a therapeutic protein that is absent or deficient in the subject. The approach targets the CCR5 locus using an sgRNA, an RNA-guided nuclease, and a homologous donor template, with homology-directed recombination mediating integration of the transgene at the CCR5 locus to direct therapeutic protein expression.
The disclosure identifies donor templates for targeted integration in CD34+ hematopoietic stem and progenitor cells, including transgenes encoding iduronidase, glucocerebrosidase, or galactocerebrosidase as a targeted alternative to random viral gene addition. Reported findings show biochemical and phenotypic correction in an MPS I mouse model, alongside lineage-restricted GCase expression and preserved long-term hematopoiesis and engraftment.
Claims Coverage
The claims define one independent claim reciting three inventive features directed to CCR5 targeting, homology-directed recombination integration, and therapeutic protein expression.
CCR5-targeted nuclease activity
An sgRNA binds to an RNA-guided nuclease and directs it to a target sequence at the CCR5 locus, cleaving the locus in a cell from a subject with a lysosomal storage disorder.
HDR integration of a therapeutic transgene
A homologous donor template comprising a transgene encoding a therapeutic protein absent or deficient in the subject integrates by homology-directed recombination at the cleaved CCR5 locus.
Therapeutic-protein expression
The integrated transgene directs expression of the therapeutic protein in the cell.
The independent claim centers on CCR5-directed cleavage, homology-directed recombination integration of a therapeutic transgene at the CCR5 locus in a subject-derived cell, and subsequent expression of the therapeutic protein.
Stated Advantages
The approach is presented as a targeted alternative to random viral gene addition.
The description reports targeted integration and sustained HSPC engraftment with IDUA expression, enzyme activity, and biochemical and phenotypic correction in an MPS I mouse model.
GBA/GCase cassettes, including a CD68S macrophage-specific promoter, are reported to support lineage-restricted GCase expression and activity in macrophages while preserving long-term hematopoiesis and engraftment.
Documented Applications
Genetic modification of cells from subjects with lysosomal storage disorders to express a therapeutic protein that is absent or deficient in the subject, including MPS I, Gaucher disease, and Krabbe disease.
Targeted integration and expression in CD34+ HSPCs using transgenes encoding iduronidase, glucocerebrosidase, or galactocerebrosidase.
Macrophage-lineage-restricted GCase expression using GBA/GCase cassettes containing a CD68S promoter.
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