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Stem Cells, Engineered Protein Reverse Stroke Damage

Berislav Zlokovic

Berislav Zlokovic (University of Southern California)

23 August 2016. A combination of stem cells and synthetic human protein was shown in lab mice to repair damaged brain cells a week after an induced stroke. An international team, led by researchers at University of Southern California, published its findings in yesterday’s issue of the journal Nature Medicine (paid subscription required).

The researchers led by physiology professor Berislav Zlokovic, are seeking a treatment for damage to brain cells and normal sensory and motor functions caused by ischemic stroke, the type of stroke that results from clots that block the flow of blood and oxygen to the brain. Ischemic stroke accounts for 85 percent of all strokes and affects some 676,000 people in the U.S. each year. Strokes of all kinds kill almost 130,000 Americans annually, or about 1 in every 20 deaths.

Zlokovic, director of USC’s Zilkha Neurogenetic Institute in Los Angeles, and colleagues developed an engineered form of activated protein C, a natural compound in humans that protects the integrity of blood vessel walls, approved by FDA in 2001 as a therapy for sepsis infections. Because the protein in its natural form also inhibits blood clotting, the treatments caused severe bleeding problems, which sharply limited its use. The researchers since began investigating an engineered and safer form of activated protein C, code-named 3K3A-APC, as a potential treatment for stroke and other neurological disorders.

The team is studying 3K3A-APC as an immediate treatment for people diagnosed with ischemic stroke, given to patients within a few hours of the stroke, to prevent further damage from occurring. ZZ Biotech LLC, a company co-founded by Zlokovic, licenses 3K3A-APC from Scripps Research Institute, its initial developer, for commercial development. The Houston company is recruiting stroke patients for an intermediate-stage clinical trial of 3K3A-APC’s safety and effectiveness.

In the new study, however, the authors are investigating 3K3A-APC’s potential to repair damaged nerve cells in the brain some time after the stroke occurred. The team previously showed in lab cultures that 3K3A-APC could stimulate production of neurons from neural stem cells, and in the new study applied the technique to lab mice 1 week following induced ischemic stroke. The 1 week period in mice is equivalent to several months in humans.

The mice were treated with neural stem cells applied next to damaged brain regions, with 4 doses of 3K3A-APC and an immunosuppressant drug over 7 days. Compared to similar mice receiving a placebo, the treated mice developed 16 times the number of stem cells. After 5 weeks, the mice were also tested for sensory and motor functions, such as walking on a rotating pod and removing adhesive tape from a front paw, with the treated mice outperforming the placebo recipients.

“Functional deficit after 5 weeks of stroke were minimized, and the mice were almost back to normal in terms of motor and sensorimotor functions,” says Zlokovic in a university statement. “Synapses formed between transplanted cells and host cells, so there is functional activation and cooperation of transplanted cells in the host circuitry.”

The authors believe the technique can be applied to a number of other neurological disorders, such as spinal cord injuries. ZZ Biotech also acquired intellectual property for 3K3A-APC’s use in wound healing, and plans to test the protein as a treatment for diabetic foot ulcers.

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