So we don't know if these stem cells even survived the journey to the brain, which means we have NO CLUE how stems cells even work. Without that knowledge ALL stem cell research is useless.
Autologous Stem Cells Found Safe for Chronic Stroke, but Evidence for Efficacy Is Slim
By Richard Robinson
February 18, 2021
Article In Brief
Intravenous administration of autologous mesenchymal stem cells were safe for chronic stroke patients when administered with mannitol to open blood-brain barrier. The trial did not show overall clinical benefit, but those patients who had a worse prognosis for recovery experienced functional improvements in their lower extremities.
Good responder rate in motor recovery in each group according to predictions at baseline: (A) Total number of stroke patients. (B) Poor predicted outcome group according to PREP. (C) Poor predicted outcome group according to PREP II; 1, FMA-T (Total score of Fugl-Meyer assessment (FMA); 2, FMA-UL (Upper limb score of FMA); 3, FMA-LL (Lower limb score of FMA).
Few therapeutic options besides ongoing rehabilitation are available for stroke patients who have residual deficits after the acute phase passes. Stem cells, with their multiple (and not fully understood) healing properties, have emerged as a potential therapy, but the optimal timing, administration route, patient selection, and other critical variables have not been definitively worked out.
A new study published in the January 20 online issue of Neurology shows, however, that autologous mesenchymal stem cells (MSCs), when administered with a treatment to open the blood-brain barrier, were safe for patients with moderate-to-severe chronic stroke. While the trial did not demonstrate any overall clinical benefit in disability and functional outcome with MSCs at 90 days, those patients who were given a worse prognosis for recovery had larger functional improvements, particularly in the motor function of the lower extremities, potentially highlighting a subset of patients for whom this treatment may hold promise.
“One of the attractive things about stem cells is that there are multiple mechanisms, which can vary with the type of cell and the timing and mode of delivery,” commented Lawrence R. Wechsler, MD, FAAN, professor of neurology at the University of Pennsylvania and chair of neurology at Pennsylvania Hospital in Philadelphia, who was not involved with the new study. Potential mechanisms include reducing inflammation, increasing angiogenesis and neurogenesis, reducing scar tissue, and enhancing function of remaining cells in the area surrounding the infarct.
“We don't believe that the generation of new neurons is a very likely mechanism, particularly for the MSCs,” he said, due to their short lifespan and the daunting complexity of resurrecting functional circuitry. “That's a long-term goal of cell therapy, but in this stage we are focusing on these other mechanisms.”
Study Design, Findings
Oh Young Bang, MD, PhD, professor of neurology at Samsung Medical Center at Sungkyungkwan Medical Center in Seoul, South Korea, led the current trial. The trial was open-label, Dr. Bang explained, because it required bone marrow aspiration to harvest MSCs, and a sham aspiration would create risks and pain for control patients that could not be justified.
The trial was randomized, however, with a control group receiving standard medical care. The investigators, who were blinded to the treatment groups, randomized patients with persistent moderate-to-severe neurological deficits about 20 days after their stroke. They performed bone marrow aspiration within a week of randomization, after which cells were cultured, expanded, and purified for transplantation back into the patient, a process that took from two to four weeks, Dr. Bang said.
Thirty-nine patients underwent bone marrow aspiration, and 15 patients, matched for age, sex, and stroke severity at randomization, served as controls. MSCs were delivered intravenously, preceded by intravenous mannitol to help open the blood-brain barrier.
The primary endpoint was a categorical shift in the modified Rankin Scale (mRS) score 90 days after randomization. Multiple secondary endpoints were included—testing motor function and ambulation, along with neuroimaging and motor evoked potential measurements of cortical excitability.
There was no significant difference between groups on the primary outcome measure, Dr. Bang said. About one third of each group experienced no change in the mRS score, while the rest of each group improved by one or two points, with a slightly higher percentage improving by two points in the control group versus the treatment group.
Similarly, there was no difference between groups in various functional outcome measures, and only one difference in motor function: the treated group improved much more on the leg score of the Motricity Index than did the control group.
Dr. Bang applied PREP I and PREP II algorithms— combining measures of motor function, evoked potentials, and diffusion tensor imaging—to assess subgroup patients according to their predicted motor recovery in the absence of treatment. These validated algorithms predict degree of recovery at 12 weeks. Comparing the PREP prediction to the actual degree of recovery, Dr. Bang found that about one-third of the patients in the experimental group who were predicted to experience poor outcomes showed clinical improvement in motor function in the lower (but not in the upper) extremities, compared with no patients in the control group.
“In patients with middle cerebral artery territory infarction, disability of the upper extremity was usually more severe than that of the lower extremity,” the study authors wrote. “In addition, while the integrity of the lateral corticospinal tract is mostly related to upper extremity motor function recovery in stroke patients, MSC treatment may affect the descending motor pathways alongside the lateral corticospinal tract.”
“We saw that intravenous application of autologous MSCs is safe but cannot be recommended in patients with chronic severe stroke based on the results of this trial.”
—DR. OH YOUNG BANG
The timing of the intervention may be important for stem cell therapy trials for stroke patients, the study authors suggested, adding that an optimal time for application of MSCs “for stem cell tropism toward the infarcted brain, enhancement of neurogenesis, and scar formation, should be determined.”
“We have learned from this trial that the response to treatment varied greatly among patients, and that selection of optimal patients for treatment and detailed and objective measures are important in a trial of stem cell therapy,” Dr. Bang said. “We saw that intravenous application of autologous MSCs is safe but it cannot be recommended in patients with chronic severe stroke based on the results of this trial.”
Expert Commentary
“This trial provides further data on the safety of marrow stromal cells in stroke patients but lacked some of the highest standards of rigorously designed trials,” commented Sean I. Savitz, MD, professor of neurology at McGovern Medical School at the University of Texas Health Science Center at Houston.
“There was no blinding with the use of a sham procedure in the study, when we know that sham procedures are possible and have been published in stem cell clinical trials involving autologous bone marrow cells,” Dr. Savitz said. “The patients therefore knew what treatment they received, which could have influenced the primary outcome on the mRS scores.
“The administration of mannitol is puzzling,” he added, “because most of the recent literature has seriously debunked the notion that substantial numbers of marrow stromal cells enter the brain, as they are trapped within peripheral organs such as the lungs after intravenous delivery. Advanced-stage, rigorously designed trials remain to be implemented to answer the question definitively of whether marrow stromal cells or other cell-based therapies improve clinical outcomes in stroke patients at various different time periods after stroke.”
Dr. Wechsler of the University of Pennsylvania was less critical of the use of mannitol. “It is a little unusual, but is very creative,” he said, as a way to promote cell uptake by the brain in patients beyond the acute phase, after the integrity of the blood-brain barrier has restored. Whether cells in fact entered the brain in this trial was not determined, he noted, and it may be that the peripheral anti-inflammatory action played a significant role.
While the use of autologous cells has the theoretical advantage of lower immunogenicity than allogeneic cells, Dr. Wechsler said that MSCs in general, even from another person, promote less immune reaction than other cells. Instead, he said, “There is probably an advantage to the allogeneic route, given both the pain and risk of bone marrow aspiration, and the time lag needed to expand the cells before returning them to the patient. With the allogeneic approach, the treatment can be taken off the shelf and administered when needed.”
An important contribution of the study, Dr. Wechsler said, was its use of the predictive algorithms to stratify patients in assessing their response. “To me, that was the most interesting outcome of the study. Can we select those patients who have potential to recover who, without treatment, wouldn't reach that potential?”
The lack of overall benefit from treatment was disappointing, but early equivocal results are nothing new in neurology, Dr. Wechsler pointed out, citing the lack of clear benefit in early trials of endovascular therapy. “But once the optimal patients were identified and selected for trial, then the potential of the treatment became clear. This is a different kind of treatment, and probably will not be as dramatic an effect, but the concept is similar. The first step is to identify those most likely to benefit.”
“Cell therapy for chronic stroke is an exciting field,” Dr. Wechsler continued. “ We are dealing with an area in which there are very few if any treatments for patients with residual deficits. I think cell therapy is probably the most promising possibility we have right now on the horizon to address this very important and unmet need.”
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