How CRISPR, Nasal Septum Cells, and Gut Bacteria Can Help Treat Arthritis

Over 100 types of arthritis exist, but most people are affected by rheumatoid arthritis and osteoarthritis. The symptoms of these two common forms can be similar, but their causes are different and, therefore, treatments also differ.

Rheumatoid arthritis is a chronic disease resulting in joint swelling, pain, and inflammation. It’s an autoimmune disorder, meaning that the immune system malfunctions, attacking the body instead of intruders – in this case, the tissue at the joints; more specifically, the synovial membrane that protects and encases the joints. The condition often affects several joints simultaneously, with inflammation making movement painful and restrictive while damaging cartilage and eventually bone. The pain can be debilitating, and the disease is hard to treat.

Osteoarthritis is more common. It occurs when the smooth cartilage joint surface wears out due to mechanical wear and tear on joints. Osteoarthritis tends to begin in one isolated joint, unlike rheumatoid arthritis. However, both types may start at any time in life. The cartilage degradation can result in severe pain and compromised mobility. A prosthetic implant is the current therapeutic approach when osteoarthritis has become fierce, which has limited durability – a problem for younger patients especially.

Scientists still don’t fully understand what initiates arthritis and how it accelerates, albeit knowing some environmental and genetic factors involved in its development. That’s why several studies worldwide are focused on finding answers to help people affected. There being so many varieties is another challenge in and of itself – each team can only focus on one kind of arthritis at a time because the treatments are type-specific.

Recent research has targeted treatment opportunities using gene editing and graft implants and exploring how gut bacteria might be involved in arthritis development. The researchers of the microbiome study suggest that the growth of harmful bacteria in the gut might be involved with initiating the disease. The following three studies involve gene editing, grafting, and microbiome analysis to answer the yet unknown aspects of rheumatoid arthritis and osteoarthritis.

Drug Releasing Stem Cell Implants

A microscopic image of an implant made of a woven scaffold coated with engineered cartilage cells programmed to release a drug in response to inflammation.
A microscopic image of an implant made of a woven scaffold coated with engineered cartilage cells programmed to release a drug in response to inflammation. (Credit: Washington University in St. Louis)

Rheumatoid arthritis is a taxing condition that affects approximately 1.3 million adults in the United States alone. Some medical experts believe that the disease begins when the immune system becomes “confused” after a viral or bacterial infection and starts attacking the joints. This battle causes inflammation and can spread to other areas of the body, resulting in symptoms unrelated to your joints like fever and fatigue.

Years ago, scientists found that tumor necrosis factor (TNF) and interleukin-1 (two of the body’s chemicals related to inflammation) trigger other parts of the immune system. Hence why medicines that block them can improve the symptoms and prevent further joint damage. However, the drugs wear away quickly and usually don’t make it to target sites fast enough unless taken in larger doses which can be toxic, causing unpleasant side effects.

Researcher Christine Pham, MD, the Guy and Ella Mae Magness Professor of Medicine and the director of the Division of Rheumatology, said:

Although biologics have revolutionized the treatment of inflammatory arthritis, the continuous administration of these drugs often leads to adverse events, including an increased risk of infection. Therefore, the idea of delivering such drugs essentially on-demand in response to arthritis flares is extremely attractive to those of us who work with arthritis patients because the approach could limit the adverse effects that accompany continuous high-dose administration of these drugs.

So, striving to improve upon rheumatoid arthritis therapies, scientists at St. Louis’s Washington University School of Medicine developed an experimental new treatment. It involves implanted stem cells reprogrammed using CRISPR-Cas9 genome editing technology to secrete such anti-inflammatory drugs only when they sense inflammation. They tested it in mice with the disease and found that the genetically engineered cells can deliver a biological drug in response to inflammation. Moreover, the therapy reduced inflammation and prevented bone erosion in the rheumatoid arthritis mouse models.

Co-first author Yunrak Choi, MD, who is a visiting orthopedic surgeon in Guilak’s lab, added:

We focused on bone erosion because that is a big problem for patients with rheumatoid arthritis, which is not effectively treated by current biologics. So we used imaging techniques to closely examine bones in the animals, and we found that this approach prevented bone erosion. So we’re very excited about this advance, which seems to meet an important unmet clinical need.

The drug they used binds to interleukin-1 (IL-1), reducing inflammation in joints. IL-1 is a substance in the body that promotes inflammation by activating a joint’s inflammatory cells. The team succeeded in keeping the drug focused on the right spot longer than via injection or infusion by implanting Stem cells Modified for Autonomous Regenerative Therapy (SMART) cartilage cells filled with genetically engineered pluripotent stem cells (iPSCs) into joints.

The SMART cartilage cells are embedded into a scaffolding material that can be implanted. The iPSCs were modified to sense inflammation around them and respond by releasing the anti-inflammatory drug. The SMART cartilage cells can survive for months or longer, delivering medications only when they’re needed.

Senior investigator Farshid Guilak, Ph.D., who is also a Professor of Orthopaedic Surgery and research director at Shriners Hospitals for Children, said:

Doctors often treat patients who have rheumatoid arthritis with injections or infusions of anti-inflammatory biologic drugs, but those drugs can cause significant side effects when delivered long enough and at high enough doses to have beneficial effects. We used CRISPR technology to reprogram the genes in stem cells. Then we created a small cartilage implant by seeding the cells on woven scaffolds, and we placed them under the skin of mice. The approach allows those cells to remain in the body for a long time and secrete a drug whenever inflammation flares. The cells sit under the skin or in a joint for months, and when they sense an inflammatory environment, they are programmed to release a biologic drug.

The most intriguing part of working with CRISPR-Cas9 gene editing is that cells can be programmed to make all sorts of drugs. Therefore, if one arthritis drug works better than another in a particular patient, scientists could make personalized treatments by engineering cartilage cells specific to that patient. Furthermore, it’s a promising strategy to treat other inflammatory arthritis conditions, too, such as juvenile arthritis – an illness affecting over 300,000 children in the United States alone.

Co-first author Kelsey H. Collins, Ph.D., who is a postdoctoral research associate in Guilak’s lab, said:

Many arthritis patients have to self-administer these drugs, giving themselves injections daily, weekly or biweekly, while others go to a doctor’s office every few months to receive an infusion of one of these biologics, but in this study, we’ve demonstrated that we can make living tissue into a drug-delivery system. These cells can sense problems and respond by producing a drug. This approach also helps us understand why certain biologics may have limited effects in inflammatory arthritis. It’s not because they don’t bind to the right target but likely because an injected drug is short-lived compared to the automatically controlled levels of drug released by implanted SMART cells.

The team hopes the technique will eventually replace regular drug injections administered to treat rheumatoid arthritis. As such, they continue to experiment with stem cells and CRISPR-Cas9. In addition, they are currently investigating if it’s possible to engineer cells that can manufacture more than one drug to respond to varying triggers of inflammation. For now, the strategy is still a long way off from human use, having only yet been tested in mice. Nevertheless, the new approach has shown very positive results with the animals and could lead to better treatments soon.

Relieving Rheumatoid Arthritis Via the Gut

How CRISPR, Nasal Septum Cells, and Gut Bacteria Can Help Treat Arthritis
(Credit: lightsource / Depositphotos)

Previous studies have reported links between rheumatoid arthritis and gut microbiome abnormalities, including associations between the population increase of certain harmful bacteria and arthritis severity. However, precisely how the gut bacteria influence joint inflammation has been unclear until now, thanks to an impressive study led by a group from University College London (UCL). Their research suggests that bacterial imbalances may initiate the development of rheumatoid arthritis by damaging and weakening the gut lining, enabling bacteria to get out and cause joint inflammation. Their findings could lead to a new approach to treating the disease.

The UCL researchers used mouse models and patient samples in the pre-clinical study proposing that restoring the gut barrier could offer a therapeutic approach to reducing symptoms’ severity of rheumatoid arthritis. Unfortunately, the mice engineered to develop collagen-induced arthritis and a genetic predisposition to gut permeability developed signs of severe arthritis. However, a different mouse model with arthritis but improved gut permeability displayed reduced joint swelling.

Co-lead author Professor Claudia Mauri of UCL’s Division of Infection and Immunity said:

We wanted to know what was happening in the gut and whether changes to the intestinal lining – which usually acts as a barrier to protect the body from bacteria – are a feature of the disease and contribute to its development.

Next, the team looked at human patient samples and found that those who have rheumatoid arthritis had higher blood levels of intestinal fatty acid-binding protein, lipopolysaccharide (LPS), and LPS binding protein (LBP). These three molecules are known biomarkers of gut damage. In particular, the researchers found that LBP levels correlate directly with acute disease severity.

Furthermore, these blood markers were higher than healthy people even at the earliest stages of arthritis, with the levels getting higher the more the disease progressed. Also, the gut lining became ‘leaky,’ enabling the passage of bacteria across the lining into the body, thus, enhancing inflammation in the gut and beyond like in the joints.

The authors explain in the newly published study:

In arthritis, there is profound damage to the gut lining, which fails to work properly as a barrier, as well as an accumulation in the gut of white blood cells that cause inflammation. The authors show that, in arthritis, bacteria cross the prohibited border of the intestinal lining and that repairing gut permeability defects with specific drugs inhibits joint inflammation.

While the study reveals that modulating gut permeability can impact the severity of joint inflammation, it doesn’t explain the chain of mechanisms linking this weakening of the gut lining to arthritis. Therefore, further studies are underway to find the missing pieces of the relationship. Regardless, their findings indicate that the gut could be a valuable therapeutic target and improve gut permeability, a compelling new treatment model.

Mauri concluded:

Our findings suggest that the intestinal lining is a therapeutic target. Importantly, we found that using existing drugs that restore the gut-barrier integrity, i.e., prevent the gut from becoming leaky or inhibit inflammatory cells from moving to and from the gut, could reduce the severity of arthritis in pre-clinical models.

 

Current treatments for rheumatoid arthritis don’t appear to correct the problems in the gut and so may leave the patient susceptible to reactivation of disease from the continuing inflammation in that area. As we advance, we need to evaluate the therapeutic impact of treating the intestinal lining of rheumatoid arthritis patients in addition to their joints. Maintaining gut health both through diet and pharmacological intervention may be a valuable new strategy.

The microbiome has been linked to several other health issues in recent years including, longevity, obesity, ALS, feelings of loneliness and levels of wisdom, conditions related to the brain and the central nervous system, and more.

Relieving Osteoarthritis in the Knee with Nasal Cartilage

How CRISPR, Nasal Septum Cells, and Gut Bacteria Can Help Treat Arthritis
The graft is tailored to the size and shape of the cartilage defect in the knee. (Credit: University of Basel, Christian Flierl)

New research by a group from Switzerland’s University Hospital Basel and the University of Basel shows that cartilage cells from the nasal septum can help repair cartilage injuries in the knee. Not only does it withstand the chronic inflammatory tissue environment in osteoarthritis, but it can even counteract the inflammation.

The research team at the University’s Department of Biomedicine, led by Professor Ivan Martin and Professor Andrea Barbero, has been cultivating cartilage tissue from cells of the nasal septum and using it to repair articular cartilage in the knee. They’ve already succeeded in initial clinical studies on isolated cartilage damage, reporting that the method could be suitable for degenerative joint diseases. If so, it’ll be a far better approach than the current practice of prosthetic implants, which we’ve already addressed as being problematic due to their limited durability.

Nasal septum cells, found in the cartilage between the nostrils, possess unique capabilities. They differ from the cells found in the articular cartilage of joints in that they lack the genes that inhibit reproduction. Therefore, they can grow and form cartilage more efficiently even as we age.

How CRISPR, Nasal Septum Cells, and Gut Bacteria Can Help Treat Arthritis
A cultivated graft ready for implantation. (Credit: University of Basel, Christian Flierl)

The team’s previous study extracted nasal septum cells of test subjects and applied them to a biocompatible scaffold. The growing cells colonized the scaffold, forming a graft that the researchers then used to replace damaged articular cartilage in the subjects’ knees. It endured the

The implant proved capable of enduring a high mechanical load, but they still didn’t know if the technology could take on the degenerative joints caused by osteoarthritis. To figure that out, the team subjected their engineered cartilage to inflammatory factors in mouse models. They wanted to make sure the grafts could withstand the chronic inflammatory tissue conditions of osteoarthritis. The new experiments showed that the engineered cartilage could withstand the harsh conditions and even actively neutralized some of the inflammatory reactions.

Scientists believe this effect is related to the unique plasticity and regenerative abilities of nasal cartilage cells. Martin explained:

Indeed, we discovered that tissue engineered from nasal cartilage cells proved to be robust at inflammatory conditions and even seemed to counteract the inflammatory reactions.

 

This effect could be due to the fact that a molecular signaling pathway, the WNT signaling pathway, was repressed by the presence of the nasal cartilage cells. This pathway is chronically upregulated in osteoarthritis and attributed to the higher expression of inflammatory factors. Therefore, repressing this pathway could account for the ability of nasal chondrocytes to counter the inflammatory conditions.

Next, the team tested the technique on a couple of young patients with severe osteoarthritis. The subjects received cartilage implants engineered from their own nasal cells. Both reported an improvement in quality of life thanks to a decrease in pain. Furthermore, MRI scans showed a sign of joint recovery – the bones in the knee joint had shifted further apart.

Implantation
Implantation. (Credit: University of Basel, Christian Flierl)

Martin concluded:

Our results have enabled us to lay the biological foundation for a therapy, and we are cautiously optimistic.

From here, the scientists will assess the treatment further through large, in-depth clinical trials. They also plan to develop the method further to treat other types of osteoarthritis that affect other joints, including the ankles and shoulders.

Read more here: Source link