CIRM-funded spinal cord injury trial keeping a steady pace

Taking an idea for a stem cell treatment and developing it into a Food and Drug Administration-approved cell therapy is like running the Boston Marathon because it requires incremental progress rather than a quick sprint. Asterias Biotherapeutics continues to keep a steady pace and to hit the proper milestones in its race to develop a stem cell-based treatment for acute spinal cord injury.

Just this week in fact, the company announced an important safety milestone for its CIRM-funded SciStar clinical trial. This trial is testing the safety and effectiveness of AST-OPC1, a human embryonic stem cell-derived cell therapy that aims to regenerate some of the lost movement and feeling resulting from spinal cord injuries to the neck.

Periodically, an independent safety review board called the Data Monitoring Committee (DMC) reviews the clinical trial data to make sure the treatment is safe in patients. That’s exactly what the DMC concluded as its latest review. They recommended that treatments with 10 and 20 million cell doses should continue as planned with newly enrolled clinical trial participants.

About a month ago, Asterias reported that six of the six participants who had received a 10 million cell dose – which is transplanted directly into the spinal cord at the site of injury – have shown improvement in arm, hand and finger function nine months after the treatment. These outcomes are better than what would be expected by spontaneous recovery often observed in patients without stem cell treatment. So, we’re hopeful for further good news later this year when Asterias expects to provide more safety and efficacy data on participants given the 10 million cell dose as well as the 20 million cell dose.

It’s a two-fer: SMART cells that make cartilage and release anti-inflammation drug
“It’s a floor wax!”….“No, it’s a dessert topping!”
“Hey, hey calm down you two. New Shimmer is a floor wax and a dessert topping!”

Those are a few lines from the classic Saturday Night Live skit that I was reminded of when reading about research published yesterday in Stem Cell Reports. The clever study generated stem cells that not only specialize into cartilage tissue that could help repair arthritic joints but the cells also act as a drug dispenser that triggers the release of a protein that dampens inflammation.

Using CRISPR technology, a team of researchers led by Farshid Guilak, PhD, at Washington University School of Medicine in St. Louis, rewired stem cells’ genetic circuits to produce an anti-inflammatory arthritis drug when the cells encounter inflammation. The technique eventually could act as a vaccine for arthritis and other chronic conditions. Image: ELLA MARUSHCHENKO

The cells were devised by a research team at Washington University School of Medicine in St. Louis. They started out with skin cells collected from the tails of mice. Using the induced pluripotent stem cell technique, the skin cells were reprogrammed into an embryonic stem cell-like state. Then came the ingenious steps. The team used the CRISPR gene-editing method to create a negative feedback loop in the cells’ inflammation response. They removed a gene that is activated by the potent inflammatory protein, TNF-alpha and replaced it with a gene that blocks TNF-alpha. Analogous experiments were carried out with another protein called IL-1.

Rheumatoid arthritis often affects the small joints causing painful swelling and disfigurement. Image: Wikipedia

Now, TNF-alpha plays a key role in triggering inflammation in arthritic joints. But this engineered cell, in the presence of TNF-alpha, activates the production of a protein that inhibits the actions of TNF-alpha. Then the team converted these stem cells into cartilage tissue and they went on to show that the cartilage was indeed resistant to inflammation. Pretty smart, huh? In fact, the researchers called them SMART cells for “Stem cells Modified for Autonomous Regenerative Therapy.” First author Dr. Jonathan Brunger summed up the approach succinctly in a press release:

“We hijacked an inflammatory pathway to create cells that produced a protective drug.”

This type of targeted treatment of arthritis would have a huge advantage over current anti-TNF-alpha therapies. Arthritis drugs like Enbrel, Humira and Remicade are very effective but they block the immune response throughout the body which carries an increased risk for serious infections and even cancer.

The team is now testing the cells in animal models of rheumatoid arthritis as well as other inflammation disorders. Those results will be important to determine whether or not this approach can work in a living animal. But senior Dr. Farshid Guilak also has an eye on future applications of SMART cells:

“We believe this strategy also may work for other systems that depend on a feedback loop. In diabetes, for example, it’s possible we could make stem cells that would sense glucose and turn on insulin in response. We are using pluripotent stem cells, so we can make them into any cell type, and with CRISPR, we can remove or insert genes that have the potential to treat many types of disorders.”