CRISPR-Based Epigenome Editing and the Potential to Treat Intervertebral Disc Pathologies: Cytokine Receptors, Cell Survival, and DRG Innervation

Abstract

Degenerative disc disease (DDD) is a primary contributor to low-back pain, a leading cause of disability. Progression of DDD is aided by inflammatory cytokines in the intervertebral disc (IVD), particularly TNF-α and IL-1β.

Learning Objectives

As a result of participating in this activity, learners will be able/better able to:

Account for the role of neuroinflammation upon discogenic pain
Utilize an improved understanding of the multiplexed nature of mechanisms of discogenic pain to better treat patients with disc degeneration.

Desirable Physician Attributes

Medical Knowledge [ACGME/ABMS] about established and evolving biomedical, clinical, and cognate (e.g. epidemiological and social-behavioral) sciences and the application of this knowledge to patient care
Employ Evidence-based Practice [IOM] Integrate best research with clinical expertise and patient values for optimum care and participate in learning and research activities to the extent feasible
Patient Care [ACGME/ABMS] Provide care that is compassionate, appropriate and effective for the treatment of health problems and the promotion of health

Accreditation & Designation

Release date: This activity was released 8/27/2021.

Termination date: The content of this activity was eligible for CME Credit until 8/26/2024.

Neurovations Education is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

Neurovations Education designates this other activity (blended learning) for a maximum of 0.75 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

This activity includes discussions of unlabeled or investigational uses of commercial and/or developmental products.

This activity includes discussions and explorations of new and evolving topics. Such inclusion includes adequate justifications of statements based upon current science, evidence and clinical reasoning.

Disclosure of Financial Relationships

Neither the presenter, reviewers nor any other person with control of, or responsibility for, the planning, delivery, or evaluation of accredited continuing education has, or has had within the past 24 months, any financial relationship(s) to disclose with ineligible companies whose primary business is producing, marketing, selling, re-selling, or distributing healthcare products used by or on patients.

Additional Reading

Farhang, N., Silverman, L., & Bowles, R. D. (2020). Improving cell therapy survival and anabolism in harsh musculoskeletal disease environments. Tissue Engineering Part B: Reviews, 26(4), 348-366.
Farhang, N., Brunger, J. M., Stover, J. D., Thakore, P. I., Lawrence, B., Guilak, F., ... & Bowles, R. D. (2017). CRISPR-based epigenome editing of cytokine receptors for the promotion of cell survival and tissue deposition in inflammatory environments. Tissue Engineering Part A, 23(15-16), 738-749.
Farhang, N., Ginley-Hidinger, M., Berrett, K. C., Gertz, J., Lawrence, B., & Bowles, R. D. (2019). Lentiviral CRISPR epigenome editing of inflammatory receptors as a gene therapy strategy for disc degeneration. Human Gene Therapy, 30(9), 1161-1175.
Stover, J. D., Farhang, N., Berrett, K. C., Gertz, J., Lawrence, B., & Bowles, R. D. (2017). CRISPR epigenome editing of AKAP150 in DRG neurons abolishes degenerative IVD-induced neuronal activation. Molecular Therapy, 25(9), 2014-2027.
Krupkova, O., Cambria, E., Besse, L., Besse, A., Bowles, R., & Wuertz‐Kozak, K. (2018). The potential of CRISPR/Cas9 genome editing for the study and treatment of intervertebral disc pathologies. JOR spine, 1(1), e1003.
Farhang, N., Davis, B., Weston, J., Ginley-Hidinger, M., Gertz, J., & Bowles, R. D. (2020). Synergistic CRISPRa-Regulated Chondrogenic Extracellular Matrix Deposition Without Exogenous Growth Factors. Tissue Engineering Part A, 26(21-22), 1169-1179.
Ede, D., Davidoff, N., Blitch, A., Farhang, N., & Bowles, R. D. (2018). Microfluidic flow cell array for controlled cell deposition in engineered musculoskeletal tissues. Tissue Engineering Part C: Methods, 24(9), 546-556.
Stover, J. D., Farhang, N., Lawrence, B., & Bowles, R. D. (2019). Multiplex Epigenome Editing of Dorsal Root Ganglion Neuron Receptors Abolishes Redundant Interleukin 6, Tumor Necrosis Factor Alpha, and Interleukin 1β Signaling by the Degenerative Intervertebral Disc. Human Gene Therapy, 30(9), 1147-1160.
Cambria, E., Arlt, M. J., Wandel, S., Krupkova, O., Hitzl, W., Passini, F. S., ... & Wuertz-Kozak, K. (2020). TRPV4 Inhibition and CRISPR-Cas9 Knockout Reduce Inflammation Induced by Hyperphysiological Stretching in Human Annulus Fibrosus Cells. Cells, 9(7), 1736.
Adams, M. A., Stefanakis, M., & Dolan, P. (2010). Healing of a painful intervertebral disc should not be confused with reversing disc degeneration: implications for physical therapies for discogenic back pain. Clinical Biomechanics, 25(10), 961-971.
Albrecht, D., Ahmed, S., Kettner, N., Borra, R., Cohen-Adad, J., Deng, H., ... & Zhang, Y. (2018). Neuroinflammation of the spinal cord and nerve roots in chronic radicular pain patients. Pain, 159(5), 968.
Tennant, F. (2019). Glial cell activation and neuroinflammation: how they cause centralized pain. Pract Pain Manag, 14, 1-10.
Echeverria-Villalobos, M., Mitchell, J., Fiorda-Diaz, J., & Weaver, T. (2021). Effects of Dorsal Column Spinal Cord Stimulation on Neuroinflammation: Revisiting Molecular Mechanisms and Clinical Outcomes on Chronic Lumbar/Leg Pain and Failed Back Surgery Syndrome. Journal of Pain Research, 14, 2337.