November 10-15

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ACR Convergence 2023

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Genome engineering can correct rheumatic diseases


3 minutes

Farshid Guilak, PhD
Farshid Guilak, PhD

Current biologic therapies can slow or halt the progression of rheumatoid arthritis and other rheumatic diseases, but repairing damaged joints is more difficult.

New approaches that combine regenerative medicine, autologous stem cells, and genome engineering can repair rheumatic joints and produce self-regulating anti-inflammatory treatment to prevent future damage. Just don’t call it stem cell therapy.

“Most of the stem cell therapies that are being applied today are neither stem cells, nor are they therapies,” said Farshid Guilak, PhD, Mildred B. Simon Professor of Orthopaedic Surgery, Developmental Biology, and Biomedical Engineering, Washington University School of Medicine. “The direct delivery of stem cells has a very high chance of off-target effects.”

The literature is filled with accounts of stem cell therapy leading to uncontrolled hyperplasia, tumor formation, infection, even a mucus-secreting nose growing in spinal tissue, Dr. Guilak said.

He discussed a very different approach during the Oscar S. Gluck, MD Memorial Lecture: Engineering the Genome to Treat Rheumatic Diseases. Registered ACR Convergence 2020 attendees can watch a reply of the session through March 11.

Instead of injecting stem cells, Dr. Guilak uses autologous stem cells to regenerate cartilage outside the body. The new cartilage is then implanted to restore function.

Preclinical systems can add rewritten genomes to the engineered cartilage. These engineered stem cells produce natural analogs to biologics such as anakinra to block inflammatory flares in a tunable, self-regulating system that eliminates pain and prevents joint damage.

Engineered tissue requires some sort of physical guide, a scaffold, in order to grow into the proper shape. Depending on the tissue needed, gels or nonwoven fibrous polymers may be appropriate. Woven textiles or three-dimensional printed scaffolds have also been used.

Dr. Guilak uses three-dimensional woven scaffolds composed of resorbable fibers similar to surgical sutures. The structure can be woven into any anatomical shape needed, from a simple focal defect to a hip joint or more complex geometries. The scaffold is infused with autologous adipose stem cells that grow into cartilage that precisely matches the scaffold. The engineered cartridge is then implanted to correct the defect and restore joint function.

The repair is not permanent.

Engineered cartilage is just as sensitive to damage from inflammation as the natural joint surface it replaced. Some sort of anti-inflammatory agent is needed to protect cartilage from future damage.

Current biologics are effective, Dr. Guilak noted, but are increasingly expensive. Suppressing immune response halts inflammatory damage but has unwelcome side effects.

“Inflammation is a necessary process,” he said. “We need resolving inflammation to fight infection and heal wounds. The problem is non-resolving inflammation where there are flares and inflammation continues for weeks and years. So we used the cartilage scaffold as a drug delivery system.”

The ideal anti-inflammatory treatment is episodic, spiking to suppress rheumatic flares and halting when the flare ends. Instead of weaving drug-eluting fibers into the scaffold, he modified the inflammatory pathway by adding a self-regulating gene modified using CRISPR/Cas9. When an inflammatory cascade is initiated, the rewritten gene produces soluble TNF receptor1 (sTNFR1) to block the pathway and stop inflammation.

In an RA mouse model, the altered gene begins producing sTNFR1 within 20 minutes of onset of inflammation and falls off within 24 hours.

“We were able to completely eliminate pain sensitivity and reduced arthritis score by 30%,” Dr. Guilak reported. “And we completely eliminated bone erosion. This is years from clinical use, but we have proof of concept for custom-designed stem cells as gene, cellular, or tissue therapies for arthritis.”