CRISPR-Mediated SATB2 Inhibition for the Treatment of Short Bowel Syndrome

Background & Unmet Need

• Short bowel syndrome (SBS) results from surgical resection or congenital disease of the small intestine, and leads to an inability to absorb sufficient nutrients
• Over time, the remaining small bowel and colon undergo structural and functional changes to increase nutrient absorption, but ~50% of patients will require long-term total parenteral nutrition (TPN)
• Teduglutide (GLP-2 agonist) is the only FDA-approved therapy for SBS patients who are dependent on TPN
• While teduglutide led to a significant reduction in TPN frequency, only 11% of patients were completely weaned from TPN
• Unmet Need: Novel treatments for SBS patients that reduce the need for TPN and improve the ability of the remaining small bowel / colon to absorb nutrients

Technology Overview

• The Technology: Inhibition of SATB2 as a therapeutic strategy for the treatment of SBS, exemplified using CRISPR gene therapy
• The Discovery: Loss of the transcription factor SATB2 transforms colonic epithelium into ileum-like tissue in mice and human colonic organoids
• Intestinal deletion of SATB2 in mice led to significant remodeling of colonic tissue, with marked changes in tissue morphology, gene expression, and cell type composition
• PoC Data: Of note, SATB2 inhibition led to the generation of bona fide nutrient-absorbing enterocytes, with significantly enhanced nutrient absorption in Satb2cKO mice colon compared to negative control
• CRISPR-mediated deletion of SATB2 using an optimized guide RNA (gRNA) replicated the findings observed in mice, suggesting a potential therapeutic strategy for SBS patients

Technology Applications

• SATB2-targeting CRISPR gene therapy using unique gRNA to restore small bowel function in SBS patients
• Cell therapy in which colonic stem cells are harvested from the patient, modified to disrupt the SATB2 gene, and then reimplanted into patients
• Gut-targeting siRNA therapy that reduces SATB2 expression

Technology Advantages

• Inhibition of SATB2 leads to durable gut remodeling that may reduce or eliminate the need for TPN
• SATB2 inhibition may be achieved through a variety of therapeutic approaches
• A single course of treatment may be sufficient to achieve lasting results