A study published by principal investigator Berislav Zlokovic and lead author Ethan Winkler, both from the Center for Neurodegeneration and Regeneration at the University of Southern California in Los Angeles, is among a host of recent research regarding amyotrophic lateral sclerosis. The new study, which was published in PNAS, discovered reasons for the breakdown of the blood-spinal cord barrier (BSCB) that contributes to motor neuron degeneration in a mouse model of ALS.
Under normal conditions, the BSCB prevents toxic molecules in circulating blood from entering the central nervous system. But with ALS, “We know that both people and transgenic rodents afflicted with this disease develop spontaneous breakdown of the blood-spinal cord barrier,” said Dr. Zlokovic in a news release from USC. But according to Dr. Zlokovic, there is a gap in this knowledge because “how these microscopic lesions affect the development of the disease has been unclear. In this study, we show that early motor neuron dysfunction related to the disease in mice is proportional to the degree of damage to the blood-spinal cord barrier and that restoring the integrity of the barrier delays motor neuron degeneration.”
The experimental setup used mice transgenic for mutated superoxide dismutase to model ALS. Blood samples taken from these mice revealed an accumulation of blood-derived neurotoxic hemoglobin and iron, which had been leaking into the spinal cord through microvascular spinal cord lesions and causing motor neuron dysfunction. When the researchers administered warfarin (an anticoagulant) to the mice to amplify the microvascular lesions, they found that motor neuron injury increased proportionally with BSCB disruption.
“We are hopeful that we can apply these findings to the corresponding disease mechanism in people,” said Dr. Zlokovic. It is possible this desire will become a reality, because when the researchers administered an activated protein C analog (3K3A-APC, a drug developed by ZZ Biotech, Dr. Zlokovic’s start-up biotechnology company), BSCB disruption was reversed and the neurotoxic hemoglobin and iron deposits were eliminated. 3K3A-APC is currently under evaluation for use in stroke patients, indicating that it may already have efficacy in human subjects. Data from the ALS Association indicates that as many as 30,000 Americans have ALS, and approximately 15 people are diagnosed with ALS each day. No cures have been found (only one FDA-approved drug called riluzole), making Zlokovic’s work all the more impactful.