Stem Cell Therapy Improves Post-Stroke Motor Function

 But is it the stem cells or exosomes that are the reason for the benefits? Which must be why no one seems to be monitoring stem cell survival.

Application of stem cell-derived exosomes in ischemic diseases: opportunity and limitations

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Stem Cell Therapy Improves Post-Stroke Motor Function

CHICAGO — Early results from a first-in-human trial some 20 years in the making suggest that neural stem cell transplantation is safe and improves motor function starting at 1 month after treatment in patients with chronic ischemic stroke.

Almost all patients saw some improvement in the primary efficacy outcome of change in total Fugl-Meyer motor score. At 12 months, eight of 12 patients had an improvement of ≥ 10 points — considered clinically meaningful — and three other patients reached this threshold earlier.

"Patients improved at 1 month, increased at 3 months, [were] stable at 6 months, and then we saw something we never saw in any of the prior trials we've done in transplant patients — and that is increased recovery between 6 and 12 months, an 11.8-[point] improvement on average (from 9.3 points at 6 months)," said investigator Gary K. Steinberg, MD, PhD, co-director of the Stanford Stroke Center, Stanford University School of Medicine, California. 

The findings were presented on May 4 at the American Association of Neurological Surgeons (AANS) 2024 Annual Meeting.

Limited Treatment Options 

Except for vagal nerve stimulation (VNS) with intensive rehabilitation, which gained US Food and Drug Administration (FDA) approval in 2021, there is currently no treatment to restore loss of function in patients with chronic ischemic stroke. 

Steinberg and his colleagues developed a human embryonic–derived neural stem cell product (NR1 cells) 24 years ago. Preclinical data in different models from their lab and others have shown that stem cell transplantation can enhance stroke recovery. 

Twenty years later, the FDA gave the greenlight for the current phase 1/2a study in humans. 

The 18 patients were aged 18-75 years and were 6 months to 5 years out from an ischemic subcortical middle cerebral stroke. They had a modified Rankin score of 3-4 and stable motor deficit, and they had been through rehabilitation. Patients with a stroke lesion < 1 cm³ or > 100 cm³ on MRI were excluded.

The NR1 stem cells were delivered through a burr hole and stereotactically injected into the subcortical peri-infarct area while patients were awake. The open-label, dose-escalation treatment (2.5, 5, 10, and 20 million cells) included tacrolimus immunosuppression for 8 weeks. Physical therapy was encouraged but not required. 

The final patient will be transplanted in May 2024, Steinberg said.

Patients had an average score increase of 4.5 points on the lower-extremity motor Fugl-Meyer Assessment (FMA) at 12 months, which was statistically significant. 

The upper-extremity FMA score also increased significantly, by an average of 7.3 points. 

"That's better than the vagal nerve stimulation trial showed of 5.8 points on average at 90 days and our patients were worse," Steinberg said. "The Fugl-Meyer motor upper extremity [score] was 20 to 50 to get into the vagal nerve trial. That would have meant only five of our patients would have been included."

Significant gains were also seen with the stem cell therapy in 10-meter gait speed and participation in activities of daily living, measured by the Barthel Index.

Surprisingly, there was no correlation between clinical response and dose, age, sex, time of stroke to transplant, or stroke volume, Steinberg said.

Further follow-up will be conducted to confirm these results and investigate mechanisms of recovery, he said. A prospective, multicenter double-blind phase 2b study is also being planned.

'Idling' Circuits Theory

If confirmed, the findings, are "very, very important," Steinberg told Medscape Medical News because, until recently, it was believed that there's no recovery after 6 months because the patient's circuits are dead. This study seems to contradict that. 

"So, this was a paradigm shift and we've shown this in some other studies injecting into the brain," Steinberg said. "The circuits, I believe, are idling, and my theory is that they are suppressed by chronic inflammation and that somehow putting the cells in — maybe the needle has a role — releases the circuits so they can function and it catalyzes a recovery.

"You don't need the cells to survive long term. They just need to release their factors [and] stimulate this system. They jazz up the circuits, and now the circuits function again. It may be very important to combine it with physical therapy, as the VNS trial did," added Steinberg.

Adverse events among the 17 patients transplanted thus far included incisional pain or headache in most patients, nausea, fatigue, transient worsened speech in three patients, and asymptomatic chronic subdural hygroma in two patients. 

The events were very minor, all resolved spontaneously, none were related to the cells, and all were related to the surgical procedure, Steinberg said. No severe adverse events requiring hospitalization occurred in the first year.

Cautious Optimism

Commenting on the findings for Medscape Medical News, Jonathan Russin, MD, associate professor of neurological surgery at the University of Southern California, Pasadena, was cautious about interpreting what the study's results might mean. 

"This sort of pivotal trial for the first-in-human stem cells for stroke represents a large body of work, but I don't think there's a lot of conclusions we can draw until it's done," he said. 

In terms of possibly better upper-limb mobility with stem cell therapy than was observed in the VNS trial, Russin said that phase 1 safety trials often enroll patients with the least to lose.

"They're going to add another patient to the trial, and then they'll have to present us with the final analysis," he said. "I'm excited though. Cautiously excited." 

The study was supported by grants from the National Institutes of Health/National Institute of Neurological Disorders and Stroke and from the California Institute for Regenerative Medicine. Steinberg reports royalties from Peter Lazic US and serving as a consultant for SanBio, Zeiss, and Surgical Theater. Russin reports having no financial relationships to disclose.