Pilot Study Suggests Safety of Cell Therapy for Ischemic Stroke

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Bone marrow stem cell therapy in patients who have recently experienced ischemic stroke appears safe and shows hints of efficacy, according to a small study published online July 3, 2012, ahead of print in Stroke.

Francisco Moniche, MD, of Hospital Universitario Virgen del Rocío (Seville, Spain), and colleagues conducted a nonrandomized Phase I/II trial in 20 middle cerebral artery (MCA) stroke patients. Subjects received intra-arterial injection of bone marrow mononuclear cells in the MCA 5 to 9 days after their event (n = 10) or standard treatment (n = 10), which involved no bone marrow aspiration or sham injection. All were severely disabled at baseline, with similar characteristics between the 2 groups. Neurologists assessing outcome were blinded to each patient’s treatment allocation. Follow-up was maintained for 6 months.

No Safety Signals

Stem cell transplantation occurred at 6.4 ± 1.3 days after stroke onset. A mean 1.59 Χ 10⁸ cells were injected (including 3.38 Χ 10⁶ CD34+ cells), with a viability of 92.8%. No serious adverse events or significant hemodynamic or respiratory changes occurred during transplantation, nor did neurological function worsen just after treatment or over follow-up. In addition, diffusion-weighted MRI showed no new ischemic lesions after treatment.

At 3 months, 2 cell therapy patients experienced isolated partial seizures. Both started antiepileptic medication and had no recurrence. No death, additional stroke, or tumor formation occurred within 6 months.

Neurological function was similar in the treated and untreated groups, though by 6 months, 20% of cell therapy patients had modified Rankin Scale scores of 2 or below compared with none of those who received standard therapy (P = 0.47). Functional status did not correlate with the amount of transplanted mononuclear cells overall. However, there was a trend toward better outcomes with higher numbers of CD34+ cells; this was especially apparent at 1 month after treatment on the Barthel scale, which measures performance in activities of daily living.

Levels of β-nerve growth factor, which the paper notes “contributes to brain plasticity,” were equivalent between the groups at 4 days but higher in treated patients at 8 days (12.8 ± 2.7 ng/mL vs. 3.9 ± 2.5 ng/mL; P = 0.029). Granulocyte-macrophage colony-stimulating factor levels were unaffected by transplantation.

Questions About Efficacy, Optimal Timing Remain

Animal models of stroke have shown that bone marrow mononuclear cells “enhance endogenous neurogenesis, angiogenesis, axonal sprouting, and synaptogenesis with neurological improvement,” the researchers note. “However, few clinical studies have been done in patients with stroke.”

While the current results suggest safety, Dr. Moniche and colleagues caution that the potential for isolated partial seizure should not be dismissed. “Although a clear relationship could not be established [between cell therapy and the 2 observed events], it warrants careful surveillance in future studies,” they advise.

Moreover, the optimal timing for treatment is still unknown. Earlier treatment could plausibly “produce a greater effect on remodeling,” the investigators write, adding that such potential must be balanced against the fact that patients can be neurologically unstable soon after stroke. “We chose a 5- to 9-day time window because patients with stroke at an early subacute phase have a more stable neurological deficit but still have an active process of remodeling, and conclusions regarding the safety are more reliable,” they conclude.

Goals Parallel Cell Therapy for Myocardial Injury

In an e-mail communication, Warren Sherman, MD, of Columbia University Medical Center (New York, NY), told TCTMD that cell therapy is “very” appropriate for stroke but stressed that the idea is not new. “Multiple studies are ongoing globally, including in the United States,” he reported, adding that some are blinded and placebo controlled. However, “few have been published yet.”

Much like in cell therapy for ischemic myocardial injury, he said, “the preclinical foundations are significant and clinical approaches are varied regarding timing (acute, subacute, or chronic), stem cell source characteristics (autologous vs. allogeneic, bone marrow-derived vs. adipose vs. other), and route of administration (intra-arterial vs. direct injection).”

According to Dr. Sherman, the goals of cell therapy for ischemic stroke are twofold: limiting injury and its subsequent effects while potentially recovering function.

The current findings offer “relative confidence in the safety of the approach,” he concluded, but “[t]hey shed little light on other important issues (ie, timing and potential functional benefit).”

 

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Source:
Moniche F, Gonzalez A, Gonzalez-Marcos J-R, et al. Intra-arterial bone marrow mononuclear cells in ischemic stroke: A pilot clinical trial. Stroke. 2012;Epub ahead of print.

 

 

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