Search

EP-4739324-A2 - SELECTED RENAL CELL POPULATIONS, CHARACTERISTICS AND USES THEREOF

EP4739324A2EP 4739324 A2EP4739324 A2EP 4739324A2EP-4739324-A2

Abstract

Methods of identifying an enriched heterogeneous renal cell population having therapeutic potential, enriched heterogeneous renal cell populations having therapeutic potential and uses for same.

Inventors

  • BERTRAM, TIMOTHY, A.
  • JAIN, DEEPAK
  • NARAYAN, PRAKASH

Assignees

  • Bertram, Timothy, A.
  • Jain, Deepak
  • Narayan, Prakash

Dates

Publication Date
20260513
Application Date
20240703

Claims (20)

  1. 1. A method of identifying an enriched heterogeneous renal cell population as having a therapeutic potential, comprising: determining whether cells of the enriched heterogeneous renal cell population express at least one cell adhesion marker, wherein the at least one cell adhesion marker comprises one or more of: intercellular adhesion molecule 5 (ICAM5), melanoma cell adhesion molecule (MCAM), contactin associated protein 1 (CNTNAP1), or matrix metallopeptidase 2 (MMP2); and identifying the enriched heterogeneous renal cell population as having therapeutic potential if cells of the enriched heterogeneous renal cell population are determined to express the at least one cell adhesion marker.
  2. 2. The method of claim 1, wherein the step of determining comprises determining percentage of cells of the enriched heterogeneous renal cell population that express the at least one cell adhesion marker.
  3. 3. The method of claim 1, wherein the at least one cell adhesion marker comprises ICAM5.
  4. 4. The method of claim 2, wherein the at least one cell adhesion marker comprises ICAM5, and wherein the enriched heterogeneous renal cell population is identified as having a therapeutic potential if it is determined that greater than 0% and at most about 0.5% of cells of the enriched heterogeneous renal cell population express ICAM5.
  5. 5. The method of claim 2, wherein the at least one cell adhesion marker comprises ICAM5, and wherein the enriched heterogeneous renal cell population is identified as having a therapeutic potential if it is determined that greater than about 60% of cells of the enriched heterogeneous renal cell population express ICAM5.
  6. 6. The method of claim 1, wherein the at least one cell adhesion marker comprises MCAM.
  7. 7. The method of claim 2, wherein the at least one cell adhesion marker comprises MCAM, and wherein the enriched heterogeneous renal cell population is identified as having a therapeutic potential if it is determined that greater than about 15% and at most about 30% of cells of the enriched heterogeneous renal cell population express MCAM.
  8. 8. The method of claim 2, wherein the at least one cell adhesion marker comprises MCAM, and wherein the enriched heterogeneous renal cell population is identified as having a therapeutic potential if it is determined that greater than about 65% of cells of the enriched heterogeneous renal cell population express MCAM.
  9. 9. The method of claim 1, wherein the at least one cell adhesion marker comprises CNTNAP1.
  10. 10. The method of claim 2, wherein the at least one cell adhesion marker comprises CNTNAP1, and wherein the enriched heterogeneous renal cell population is identified as having a therapeutic potential if it is determined that greater than about 4% and at most about 15% of cells of the enriched heterogeneous renal cell population express CNTNAP1.
  11. 11. The method of claim 2, the at least one cell adhesion marker comprises CNTNAP1, and wherein the enriched heterogeneous renal cell population is identified as having a therapeutic potential if it is determined that greater than about 15% and at most about 30% of cells of the enriched heterogeneous renal cell population express CNTNAP1.
  12. 12. The method of claim 1, wherein the at least one cell adhesion marker comprises MMP2.
  13. 13. The method of claim 2, wherein the at least one cell adhesion marker comprises MMP2, and wherein the enriched heterogeneous renal cell population is identified as having a therapeutic potential if it is determined that greater than about 8% and at most about
  14. 14. The method of claim 2, wherein the at least one cell adhesion marker comprises MMP2, and wherein the enriched heterogeneous renal cell population is identified as having a therapeutic potential if it is determined that greater than about 10% and at most about 35% of cells of the enriched heterogeneous renal cell population express MMP2.
  15. 15. The method of claim 2, wherein the at least one cell adhesion marker comprises MMP2, and wherein the enriched heterogeneous renal cell population is identified as having a therapeutic potential if it is determined that greater than about 15% and at most about 35% of cells of the enriched heterogeneous renal cell population express MMP2.
  16. 16. The method of claim 1, wherein the at least one cell adhesion marker comprises: (a) ICAM5 and MCAM; or (b) ICAM5 and CNTNAP1; or (c) ICAM5 and MMP2; or (d) MCAM and CNTNAP1; or (e) MCAM and MMP2; or (f) CNTNAP1 and MMP2.
  17. 17. The method of claim 2, wherein the at least one cell adhesion marker comprises: (a) ICAM5 and MCAM, and wherein the enriched heterogeneous renal cell population is identified as having a therapeutic potential if it is determined that greater than 0% and at most about 0.5% of cells of the enriched heterogeneous renal cell population express ICAM5 and greater than about 15% and at most about 30% of cells of the enriched heterogeneous renal cell population express MCAM; or (b) ICAM5 and CNTNAP1, and wherein the enriched heterogeneous renal cell population is identified as having a therapeutic potential if it is determined that greater than 0% and at most about 0.5% of cells of the enriched heterogeneous renal cell population express ICAM5 and greater than about 4% and at most about 15% of cells of the enriched heterogeneous renal cell population express CNTNAP1; or (c) ICAM5 and MMP2, and wherein the enriched heterogeneous renal cell population is identified as having a therapeutic potential if it is determined that greater than 0% and at most about 0.5% of cells of the enriched heterogeneous renal cell population express ICAM5 and greater than about 8% and at most about 25% of cells of the enriched heterogeneous renal cell population express MMP2; or (d) MCAM and CNTNAP, and wherein the enriched heterogeneous renal cell population is identified as having a therapeutic potential if it is determined that greater than about 15% and at most about 30% of cells of the enriched heterogeneous renal cell population express MCAM and greater than about 4% and at most about 15% of cells of the enriched heterogeneous renal cell population express CNTNAP; or (e) MCAM and MMP2, and wherein the enriched heterogeneous renal cell population is identified as having a therapeutic potential if it is determined that greater than about 15% and at most about 30% of cells of the enriched heterogeneous renal cell population express MCAM and greater than about 8% and at most about 25% of cells of the enriched heterogeneous renal cell population express MMP2; or (f) CNTNAP 1 and MMP2, and wherein the enriched heterogeneous renal cell population is identified as having a therapeutic potential if it is determined that greater than about 4% and at most about 15% of cells of the enriched heterogeneous renal cell population express CNTNAP and greater than about 8% and at most about 25% of cells of the enriched heterogeneous renal cell population express MMP2.
  18. 18. The method of claim 2, wherein the at least one cell adhesion marker comprises: (a) ICAM5 and MCAM, and wherein the enriched heterogeneous renal cell population is identified as having a therapeutic potential if it is determined that greater than about 60% of cells of the enriched heterogeneous renal cell population express ICAM5 and greater than about 65% of cells of the enriched heterogeneous renal cell population express MCAM; or (b) ICAM5 and CNTNAP 1, and wherein the enriched heterogeneous renal cell population is identified as having a therapeutic potential if it is determined that greater than about 60% of cells of the enriched heterogeneous renal cell population express ICAM5 and greater than about 15% and at most about 30% of cells of the enriched heterogeneous renal cell population express CNTNAP1; or (c) ICAM5 and MMP2, and wherein the enriched heterogeneous renal cell population is identified as having a therapeutic potential if it is determined that greater than about 60% of cells of the enriched heterogeneous renal cell population express ICAM5 and greater than about 10% and at most about 35% of cells of the enriched heterogeneous renal cell population express MMP2; or (d) MCAM and CNTNAP, and wherein the enriched heterogeneous renal cell population is identified as having a therapeutic potential if it is determined that greater than about 65% of cells of the enriched heterogeneous renal cell population express MCAM and greater than about 15% and at most about 30% of cells of the enriched heterogeneous renal cell population express CNTNAP 1; or (e) MCAM and MMP2, and wherein the enriched heterogeneous renal cell population is identified as having a therapeutic potential if it is determined that greater than about 65% of cells of the enriched heterogeneous renal cell population express MCAM and greater than about 10% and at most about 35% of cells of the enriched heterogeneous renal cell population express MMP2; or (f) CNTNAP 1 and MMP2, and wherein the enriched heterogeneous renal cell population is identified as having a therapeutic potential if it is determined that greater than about 15% and at most about 30% of cells of the enriched heterogeneous renal cell population express CNTNAP1 and greater than about 10% and at most about 35% of cells of the enriched heterogeneous renal cell population express MMP2.
  19. 19. The method of claim 1, wherein the at least one cell adhesion marker comprises: (a) ICAM5, MCAM and CNTNAP1; or (b) ICAM5, MCAM and MMP2; or (c) ICAM5, CNTNAP1 and MMP2; or (d) MCAM, CNTNAP 1 and MMP2.
  20. 0. The method of claim 2, wherein the at least one cell adhesion marker comprises: (a) ICAM5, MCAM and CNTNAP1, and wherein the enriched heterogeneous renal cell population is identified as having a therapeutic potential if it is determined that greater than 0% and at most about 0.5% of cells of the enriched heterogeneous renal cell population express ICAM5, greater than about 15% and at most about 30% of cells of the enriched heterogeneous renal cell population express MCAM and greater than about 4% and at most about 15% of cells of the enriched heterogeneous renal cell population express CNTNAP1; or (b) ICAM5, MCAM and MMP2, and wherein the enriched heterogeneous renal cell population is identified as having a therapeutic potential if it is determined that greater than 0% and at most about 0.5% of cells of the enriched heterogeneous renal cell population express ICAM5, greater than about 15% and at most about 30% of cells of the enriched heterogeneous renal cell population express MCAM and greater than about 8% and at most about 25% of cells of the enriched heterogeneous renal cell population express MMP2; or (c) ICAM5, CNTNAP1 and MMP2, and wherein the enriched heterogeneous renal cell population is identified as having a therapeutic potential if it is determined that greater than 0% and at most about 0.5% of cells of the enriched heterogeneous renal cell population express ICAM5, greater than about 4% and at most about 15% of cells of the enriched heterogeneous renal cell population express CNTNAP1 and greater than about 8% and at most about 25% of cells of the enriched heterogeneous renal cell population express MMP2; or (d) MCAM, CNTNAP1 and MMP2, and wherein the enriched heterogeneous renal cell population is identified as having a therapeutic potential if it is determined that greater than about 15% and at most about 30% of cells of the enriched heterogeneous renal cell population express MCAM, greater than about 4% and at most about 15% of cells of the enriched heterogeneous renal cell population express CNTNAP and greater than about 8% and at most about 25% of cells of the enriched heterogeneous renal cell population express MMP2.

Description

SELECTED RENAL CELL POPULATIONS, CHARACTERISTICS AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of priority to U.S. Provisional Patent Application Serial No. 63/512,541, filed on July 7, 2023, and U.S. Provisional Patent Application Serial No. 63/589,934, filed on October 12, 2023. The disclosures of the above-referenced applications are herein expressly incorporated by reference it their entireties, including any drawings. BACKGROUND [0002] Chronic kidney disease (CKD) is reaching, or has reached, pandemic proportions (Thurlow JS, et al., Am J Nephrol 52(2021):98-107; Murphy D, et al., Intern Med 65(2016):473-481; Hill NR, et al., PLoS One l l:e0158765. doi: 10.1371 /journal. pone.0158765). Prevalence data from the U.S. to Europe show that approximately 10% of the general population has stage 1-3 CKD (ERA, 2009; USRDS, 2011; Jha et al., Lancet. 382(2013):260-72). CKD has increased >33% between 1996 and 2006 in the US alone (U.S. Renal Data System. Costs of CKD and ESRD. Minneapolis, MN, 2007). Meanwhile, management of CKD remains a challenge for nephrologists. Most standard-of- care treatments for CKD are small molecules targeting biochemical pathways in the kidney to affect single or related co-morbidities. However, these treatments do not affect the underlying CKD kidney’s glomerular and tubulointerstitial dysfunction. Ultimately, in patients that progress to end stage renal disease (ESRD), renal replacement therapy (RRT; dialysis or transplantation) is required for survival. There remains an unmet need for a therapeutic modality that directly addresses the diseased kidney’s tissue biology. Such a therapeutic modality can potentially arrest or even reverse CKD progression and mitigate or avert the need for RRT. [0003] Selected renal cells (SRC), a heterogeneous renal cell population enriched for renal epithelial cells, are being advanced as autologous cell-based therapy for treatment of CKD (Stavas J, et al., A J Nephrol 53(2022):50-58.; Stavas J, et al., KI Reports, in press). Derived from the donor kidney, SRC is an admixture principally of proximal tubular epithelial cells (Presnell SC, et al, Tissue Eng Part C Methods 17(2011 ) :261 -73) . Results from a Phase II clinical trial in a diabetic kidney disease cohort suggested that SRC administration is safe and is accompanied by improvement in renal function (Stavas J, et al., KI Reports, in press). [0004] There is a need in the art to identify heterogenous renal cell populations, such as SRCs, that have potential therapeutic activity, e.g., based on their capacity to drive renal tubule formation. BRIEF SUMMARY [0005] The present disclosure relates generally to a method of identifying an enriched heterogeneous renal cell population as having a therapeutic potential. In the method, it is determined whether cells of the enriched heterogeneous renal cell population express at least one cell adhesion marker. The at least one cell adhesion marker includes, or is one or more of: intercellular adhesion molecule 5 (ICAM5), melanoma cell adhesion molecule (MCAM), contactin associated protein 1 (CNTNAP1), or matrix metallopeptidase 2 (MMP2). The enriched heterogeneous renal cell population is identified as having therapeutic potential if cells of the enriched heterogeneous renal cell population are determined to express the at least one cell adhesion marker. [0006] The present disclosure describes yet another method of identifying an enriched heterogeneous renal cell population as having therapeutic potential. In the method, expression of transforming growth factor beta 2 (TGF|32) by cells of the enriched heterogeneous renal cell population is determined. The enriched heterogeneous renal cell population is identified as having therapeutic potential if it is determined that: (i) greater than about 50% of cells of the enriched heterogeneous renal cell population express TGF[32; and/or (ii) TGF[32 is secreted by cells of the enriched heterogeneous renal cell population in an amount of at least about 1.0 ng per 1,000,000 enriched heterogeneous renal cell population cells. BRIEF DESCRIPTION OF FIGURES [0007] FIG. 1 Uniform manifold approximation and projection (UMAP) to show SRC population cells that express cdhl . Pink/darker grey dots represent cells that express cdhl . Light grey dots represent cells that do not express cdhl. [0008] FIG. 2: Shows an interactome, derived from gene ontology and visualized using miRNet, formed by cell-cell adhesion markers (CDH1, CNTNAP1, PECAM1, ICAM5, MCAM, COL11A1 and MMP2) expressed by human SRCs. [0009] FIG. 3: Provides gene ontology mapping confirming that hsa-miR-145 and hsa-miR- 199a-5p regulate tgf/32 together with renal cell epithelial markers (CDH1, SLC38A2, SLC8A1) in SRCs. [0010] FIG. 4: UMAP to show SRC population cells that express tgf/32. Orange/darker grey dots represent cells that express tgf/32. Light grey dots represent cells that do not express tgf/32. [0011