Summary: Researchers use CRISPR to modulate genes in order to reduce tissue damage and inflammation for people with neck and back pain.
Source: University of Utah.
For millions of sufferers, there is nothing more debilitating than chronic back or joint pain. It can feel like a lifetime of misery.
But researchers led by University of Utah bioengineering assistant professor Robby Bowles have discovered a way to curb chronic pain by modulating genes that reduce tissue- and cell-damaging inflammation.
“This has applications for many inflammatory-driven diseases,” Bowles says. “It could be applied for arthritis or to therapeutic cells that are being delivered to inflammatory environments that need to be protected from inflammation.”
The team’s discovery was published in a new paper this month, “CRISPR-Based Epigenome Editing of Cytokine Receptors for the Promotion of Cell Survival and Tissue Deposition in Inflammatory Environments,” in a special issue of Tissue Engineering. University of Utah bioengineering doctoral student, Niloofar Farhang, co-authored the study, which is a collaborative project between the University of Utah, Duke University and Washington University in St. Louis.
In chronic back pain, for example, slipped or herniated discs are a result of damaged tissue when inflammation causes cells to create molecules that break down tissue. Typically, inflammation is nature’s way of alerting the immune system to repair tissue or tackle infection. But chronic inflammation can instead lead to tissue degeneration and pain.
Bowles’ team is using the CRISPR (Clustered Regularly Interspaced Short Palindromic Repeat) system — new technology of modifying human genetics — to stop cell death and keep the cells from producing molecules that damage tissue and result in chronic pain. But it doesn’t do this by editing or replacing genes, which is what CRISPR tools are typically used for. Instead, it modulates the way genes turn on and off in order to protect cells from inflammation and thus breaking down tissue.
“So they won’t respond to inflammation. It disrupts this chronic inflammation pattern that leads to tissue degeneration and pain,” Bowles says. “We’re not changing what is in your genetic code. We’re altering what is expressed. Normally, cells do this themselves, but we are taking engineering control over these cells to tell them what to turn on and turn off.”
Now that researchers know they can do this, doctors will be able to modify the genes via an injection directly to the affected area and delay the degeneration of tissue. In the case of back pain, a patient may get a discectomy to remove part of a herniated disc to relieve the pain, but tissue near the spinal cord may continue to breakdown, leading to future pain. This method could stave off additional surgeries by stopping the tissue damage.
“The hope is that this stops degeneration in its tracks, and the patient could avoid any future surgeries,” Bowles says. “But it’s patient to patient. Some might still need surgery, but it could delay it.”
So far, the team has developed a virus that can deliver the gene therapy and has filed a patent on the system. They hope to proceed to human trials after collecting initial data, but Bowles believes it could be about 10 years before this method is used in patients.
Other researchers on the team include University of Utah orthopaedic surgeon Brandon Lawrence, Duke University biomedical engineering associate professor Charles. A. Gersbach, biomedical engineering professor Farshid Guilak and Distinguished Professor Lori A. Setton of Washington University in St. Louis.
Source: Vince Horiuchi – University of Utah
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: Abstract for “CRISPR-Based Epigenome Editing of Cytokine Receptors for the Promotion of Cell Survival and Tissue Deposition in Inflammatory Environments” by Niloofar Farhang, Jonathan M. Brunger, Joshua D. Stover, Pratiksha I. Thakore, Brandon Lawrence, Farshid Guilak, Charles A. Gersbach, Lori A. Setton, and Robby D. Bowles in Tissue Engineering. Published online February 20 2017 doi:10.1089/ten.tea.2016.0441
[cbtabs][cbtab title=”MLA”]University of Utah “Pain in the Neck: Using CRISPR to Prevent Tissue Damage and Neck Pain.” NeuroscienceNews. NeuroscienceNews, 13 March 2017.
<https://neurosciencenews.com/crispr-neck-pain-6241/>.[/cbtab][cbtab title=”APA”]University of Utah (2017, March 13). Pain in the Neck: Using CRISPR to Prevent Tissue Damage and Neck Pain. NeuroscienceNew. Retrieved March 13, 2017 from https://neurosciencenews.com/crispr-neck-pain-6241/[/cbtab][cbtab title=”Chicago”]University of Utah “Pain in the Neck: Using CRISPR to Prevent Tissue Damage and Neck Pain.” https://neurosciencenews.com/crispr-neck-pain-6241/ (accessed March 13, 2017).[/cbtab][/cbtabs]
Abstract
CRISPR-Based Epigenome Editing of Cytokine Receptors for the Promotion of Cell Survival and Tissue Deposition in Inflammatory Environments
Musculoskeletal diseases have been associated with inflammatory cytokine action, particularly action by TNF-α and IL-1β. These inflammatory cytokines promote apoptosis and senescence of cells in diseased tissue and extracellular matrix breakdown. Stem cell-based therapies are being considered for the treatment of musculoskeletal diseases, but the presence of these inflammatory cytokines will have similar deleterious action on therapeutic cells delivered to these environments. Methods that prevent inflammatory-induced apoptosis and proinflammatory signaling, in cell and pathway-specific manners are needed. In this study we demonstrate the use of clustered regularly interspaced short palindromic repeats (CRISPR)-based epigenome editing to alter cell response to inflammatory environments by repressing inflammatory cytokine cell receptors, specifically TNFR1 and IL1R1. We targeted CRISPR/Cas9-based repressors to TNFR1 and IL1R1 gene regulatory elements in human adipose-derived stem cells (hADSCs) and investigated the functional outcomes of repression of these genes. Efficient signaling regulation was demonstrated in engineered hADSCs, as activity of the downstream transcription factor NF-κB was significantly reduced or maintained at baseline levels in the presence of TNF-α or IL-1β. Pellet culture of undifferentiated hADSCs demonstrated improved survival in engineered hADSCs treated with TNF-α or IL-1β, while having little effect on their immunomodulatory properties. Furthermore, engineered hADSCs demonstrated improved chondrogenic differentiation capacity in the presence of TNF-α or IL-1β, as shown by superior production of glycosaminglycans in this inflammatory environment. Overall this work demonstrates a novel method for modulating cell response to inflammatory signaling that has applications in engineering cells delivered to inflammatory environments, and as a direct gene therapy to protect endogenous cells exposed to chronic inflammation, as observed in a broad spectrum of degenerative musculoskeletal pathology.
“CRISPR-Based Epigenome Editing of Cytokine Receptors for the Promotion of Cell Survival and Tissue Deposition in Inflammatory Environments” by Niloofar Farhang, Jonathan M. Brunger, Joshua D. Stover, Pratiksha I. Thakore, Brandon Lawrence, Farshid Guilak, Charles A. Gersbach, Lori A. Setton, and Robby D. Bowles in Tissue Engineering. Published online February 20 2017 doi:10.1089/ten.tea.2016.0441
