Method for utilizing engineered dendritic cells to induce gut-homing regulatory T cells and treat gut inflammation
Inventors
Tang, Xiaolei • Baylink, David J. • Lau, K.-H. William • Walter, Michael
Assignees
Publication Number
US-12275961-B2
Publication Date
2025-04-15
Expiration Date
2036-02-11
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Abstract
Gene-modified, lymphoid-tissue-homing dendritic cells that comprise a 1-alpha-hydroxylase gene and a retinaldehyde dehydrogenase 2 gene, where the 1-alpha-hydroxylase gene is expressed to produce functional 1-alpha-hydroxylase enzyme and the retinaldehyde dehydrogenase 2 gene is expressed to produce functional retinaldehyde dehydrogenase 2 gene enzyme. A method for treating one or more than one inflammation-related condition or disease, the method comprising administering gene-modified, lymphoid-tissue-homing dendritic cells that comprise a 1-alpha-hydroxylase gene and a retinaldehyde dehydrogenase 2 gene, where the 1-alpha-hydroxylase gene is expressed to produce functional 1-alpha-hydroxylase enzyme and the retinaldehyde dehydrogenase 2 gene is expressed to produce functional retinaldehyde dehydrogenase 2 gene enzyme.
Core Innovation
The invention provides gene-modified, lymphoid-tissue-homing dendritic cells engineered to overexpress both a 1-alpha-hydroxylase gene (CYP27B1) and a retinaldehyde dehydrogenase 2 gene (ALDH1a2), resulting in the constitutive production of functional 1-alpha-hydroxylase and retinaldehyde dehydrogenase 2 (RALDH2) enzymes. These dendritic cells are designed to migrate to peripheral lymphoid organs upon administration, where they locally produce the active vitamin D metabolite (1,25[OH]2D) and retinoic acid (RA).
The core problem addressed by this invention is the need for a more effective and targeted therapy for inflammation-related conditions, such as inflammatory bowel diseases (IBDs), without causing the systemic side effects commonly seen with current treatments like anti-inflammatory drugs and systemic calcitriol administration. Many current therapies also suffer from low efficacy, severe side effects, and do not provide long-term remission or cure for conditions involving inappropriate inflammation.
The disclosed engineered dendritic cells induce the generation of gut-homing regulatory T (Treg) cells in peripheral lymphoid organs, which then migrate to and suppress inflammation specifically in the gut. This approach creates locally high concentrations of immunomodulatory metabolites at disease-relevant sites without elevating their levels systemically. By programming naïve T cells into gut-homing Tregs directly in peripheral tissues, the invention aims to achieve stable, organ-targeted immunoregulation for gut inflammatory diseases while preserving general immune function.
Claims Coverage
The patent contains one independent claim that forms the basis for several inventive features focusing on engineered dendritic cells with specific genetic modifications and their use in therapy.
Gene-modified dendritic cell overexpressing CYP27B1 and ALDH1a2 for gastrointestinal inflammatory disease
The main inventive feature is a gene-modified dendritic cell engineered to overexpress both a cytochrome p450 family 27 subfamily B polypeptide 1 (CYP27B1) gene, which encodes 1-alpha-hydroxylase, and an aldehyde dehydrogenase 1 family member A2 (ALDH1a2) gene, which encodes retinaldehyde dehydrogenase 2 (RALDH2). The dendritic cell is specifically configured to constitutively overexpress 1-alpha-hydroxylase, and optionally RALDH2, supporting targeted induction of gut-homing regulatory T cells for treating gastrointestinal inflammatory disease.
Bicistronic expression vector with specific promoters for gene expression
This inventive feature covers a gene-modified dendritic cell containing a bicistronic expression vector, wherein the spleen focus-forming viral (SFFV) promoter controls CYP27B1 gene expression and a phosphoglycerate kinase (PGK) promoter controls ALDH1a2 gene expression. The vector can be derived from either lentivirus or adeno-associated virus.
Gene-modified dendritic cell derived from bone marrow or peripheral blood mononuclear cells
The invention covers dendritic cells sourced from bone marrow or peripheral blood mononuclear cells (PBMCs) that have been genetically modified to overexpress CYP27B1 and ALDH1a2.
Pharmaceutical composition comprising the engineered dendritic cell
This feature relates to a pharmaceutical composition comprising the gene-modified dendritic cell and a pharmaceutically acceptable carrier, suitable for therapeutic administration in treating gastrointestinal inflammatory diseases.
Separate expression vectors for gene delivery
The invention also covers gene-modified dendritic cells comprising either a first expression vector with a CYP27B1 gene (but not an ALDH1a2 gene) and an operably linked promoter or a second expression vector with an ALDH1a2 gene (but not a CYP27B1 gene) and an operably linked promoter.
In summary, the claims protect gene-modified dendritic cells with specific overexpression of CYP27B1 and ALDH1a2, vector design with defined promoters and viral backbones, source cell type, pharmaceutical compositions thereof, and flexible approaches to vector construction and gene delivery for targeted therapy of gastrointestinal inflammatory diseases.
Stated Advantages
The invention enables targeted suppression of intestinal inflammation without compromising systemic immunity or causing systemic side effects such as hypercalcemia.
Engineered dendritic cells induce stable gut-homing regulatory T cells directly in vivo, overcoming the instability issues observed with in vitro-generated Tregs and tolerogenic DCs.
Local production of active vitamin D and retinoic acid at relevant immune sites allows effective immunomodulation without needing high systemic doses, avoiding toxicity.
A single injection of gene-modified dendritic cells may be sufficient for effective treatment, potentially reducing costs and simplifying the therapy regimen.
Documented Applications
Treatment or prevention of intestinal (gut) inflammation, including inflammatory bowel diseases such as Crohn's disease and ulcerative colitis.
Generation of gut-homing regulatory T cells to specifically suppress inflammation in the intestines.
Therapy for other inflammatory diseases in the intestines beyond IBD.
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