Lara Ionescu Silverman1, Galina Dulatova2, Terry Tandeski2, Isaac E Erickson2, Beverly Lundell3, David Toplon3, Tricia Wolff4, Antwain Howard4, Subba Chintalacharuvu4, Kevin T Foley5. 1. DiscGenics, Inc, 5940 W Harold Gatty Dr, Salt Lake City, UT 84116, USA; Department of Neurosurgery, University of Tennessee Health Science Center, Memphis, TN, USA. Electronic address: lara@discgenics.com. 2. DiscGenics, Inc, 5940 W Harold Gatty Dr, Salt Lake City, UT 84116, USA. 3. WuXi AppTec, 2540 Executive Drive, St. Paul, MN 55120, USA. 4. Covance Laboratories, 671 S. Meridian Rd, Greenfield, IN, USA. 5. DiscGenics, Inc, 5940 W Harold Gatty Dr, Salt Lake City, UT 84116, USA; Department of Neurosurgery, University of Tennessee Health Science Center, Memphis, TN, USA; Semmes-Murphey Clinic, 6325 Humphreys Blvd, Memphis, TN, USA.
Abstract
BACKGROUND/CONTEXT: Disc degeneration (DD) is a significant driver of low back pain and few treatments exist to treat the pain and disability associated with the disease. PURPOSE: Our group has developed a method to generate therapeutic discogenic cells as a potential treatment for symptomatic DD. These cells are derived and modified from adult nucleus pulposus cells. In this study, we evaluated the characteristics, mode of action, and in vivo efficacy and safety of these cells prior to human clinical testing. STUDY DESIGN: Privately funded in vitro studies and in vivo preclinical models were used in this study. METHODS: Discogenic cells generated from different adult human donors were evaluated for surface marker expression profile, matrix deposition and tumorigenic potential. Discogenic cells were then injected subcutaneously into nude mice to assess cell survival and possible extracellular matrix production in vivo. Finally, a rabbit model of DD was used to evaluate the therapeutic potential of discogenic cells after disc injury. RESULTS: We found that discogenic cells have a consistent surface marker profile, are multipotent for mesenchymal lineages, and produce extracellular matrix consisting of aggrecan, collagen 1 and collagen 2. Cells did not show abnormal karyotype after culturing and did not form tumor-like aggregates in soft agar. After subcutaneous implantation in a nude mouse model, the human discogenic cells were found to have generated regions rich with extracellular matrix over the course of 4 months, with no signs of tumorigenicity. Intradiscal injection of human discogenic cells in a rabbit model of DD caused an increase in disc height and improvement of tissue architecture relative to control discs or injection of vehicle alone (no cells) with no signs of toxicity. CONCLUSIONS: This study demonstrates that intradiscal injection of discogenic cells may be a viable treatment for human degenerative disc disease. The cells produce extracellular matrix that may rebuild the depleting tissue within degenerating discs. Also, the cells do not pose any significant safety concerns. CLINICAL SIGNIFICANCE: Human clinical testing of discogenic cells combined with a sodium hyaluronate carrier is ongoing in multiple randomized, controlled, double-blinded studies in the United States (clinicaltrials.gov identifier NCT03347708) and Japan (clinicaltrials.gov identifier NCT03955315).
BACKGROUND/CONTEXT: Disc degeneration (DD) is a significant driver of low back pain and few treatments exist to treat the pain and disability associated with the disease. PURPOSE: Our group has developed a method to generate therapeutic discogenic cells as a potential treatment for symptomatic DD. These cells are derived and modified from adult nucleus pulposus cells. In this study, we evaluated the characteristics, mode of action, and in vivo efficacy and safety of these cells prior to human clinical testing. STUDY DESIGN: Privately funded in vitro studies and in vivo preclinical models were used in this study. METHODS: Discogenic cells generated from different adult human donors were evaluated for surface marker expression profile, matrix deposition and tumorigenic potential. Discogenic cells were then injected subcutaneously into nude mice to assess cell survival and possible extracellular matrix production in vivo. Finally, a rabbit model of DD was used to evaluate the therapeutic potential of discogenic cells after disc injury. RESULTS: We found that discogenic cells have a consistent surface marker profile, are multipotent for mesenchymal lineages, and produce extracellular matrix consisting of aggrecan, collagen 1 and collagen 2. Cells did not show abnormal karyotype after culturing and did not form tumor-like aggregates in soft agar. After subcutaneous implantation in a nude mouse model, the human discogenic cells were found to have generated regions rich with extracellular matrix over the course of 4 months, with no signs of tumorigenicity. Intradiscal injection of human discogenic cells in a rabbit model of DD caused an increase in disc height and improvement of tissue architecture relative to control discs or injection of vehicle alone (no cells) with no signs of toxicity. CONCLUSIONS: This study demonstrates that intradiscal injection of discogenic cells may be a viable treatment for humandegenerative disc disease. The cells produce extracellular matrix that may rebuild the depleting tissue within degenerating discs. Also, the cells do not pose any significant safety concerns. CLINICAL SIGNIFICANCE: Human clinical testing of discogenic cells combined with a sodium hyaluronate carrier is ongoing in multiple randomized, controlled, double-blinded studies in the United States (clinicaltrials.gov identifier NCT03347708) and Japan (clinicaltrials.gov identifier NCT03955315).
Authors: Megan Co; Huiming Dong; Daniel J Boulter; Xuan V Nguyen; Safdar N Khan; Brian Raterman; Brett Klamer; Arunark Kolipaka; Benjamin A Walter Journal: J Magn Reson Imaging Date: 2022-03-15 Impact factor: 5.119
Authors: Daniel Rodriguez-Granrose; Amanda Jones; Hannah Loftus; Terry Tandeski; Will Heaton; Kevin T Foley; Lara Silverman Journal: Bioprocess Biosyst Eng Date: 2021-02-27 Impact factor: 3.210