After a stroke, extracellular matrix (ECM) molecules known as chondroitin sulfate proteoglycans (CSPGs) become barriers to axonal plasticity and precursor cell migration, thwarting nervous system repair.
Using a peptide called NVG-291-R to block a major proteoglycan receptor, researchers from two Ohio-based universities—the University of Cincinnati and Case Western Reserve University (CWRU)—showed significant behavioral recovery accompanied by neuroprotection, axonal sprouting, and neuroblast migration into the lesion in an animal model of stroke. Such biological reparations may have implications for both normal physiological function and the regenerative response of the brain after injury.
The research, “Inhibition of chondroitin sulfate proteoglycan receptor PTPσ promotes migration of newly born neuroblasts, axonal sprouting, and recovery from stroke,” was published in Cell Reports.
“We are very excited about the data showing significant improvement in motor function, sensory function, spatial learning, and memory, even when treatment was initiated as late as seven days after stroke onset,” said the senior author of the paper, Agnes (Yu) Luo, PhD, associate professor, department of molecular genetics and biochemistry at the University of Cincinnati.
Finding the right stroke treatment paradigm
Current treatment strategies for stroke, which profoundly alters affected individuals and is a leading causes of death and disability worldwide, are largely neuroprotective, and all are limited by narrow time windows. They do not, however, do much by way of regeneration. That being said, the potential for regeneration/plasticity in the post-stroke central nervous system (CNS) is still possible for weeks or even longer, which may provide an extended opportunity for treatment.
“The only current FDA-approved drug for treatment of stroke does not repair damage and must be administered within 4.5 hours of stroke onset,” Luo said. “Most therapies being researched need to be applied within 24–48 hours of a stroke’s onset. A product that works to repair damage from stroke even a week after symptom onset would change the paradigm for stroke treatment.”
NVG-291-R repairs the CNS in mice with stroke
Shortly after CNS injury, certain CSPGs are upregulated in abundance in glial scars limiting regeneration through the lesion, but also severely restrain potential neuroplasticity around and beyond the lesion perimeter. CSPGs have also been suggested to curtail the access of progenitor cells to remyelinate cord and multiple sclerosis (MS) lesions
Luo and colleagues zeroed in on the transmembrane receptor protein tyrosine phosphatase sigma (PTPσ), which has been identified as a primary receptor for the inhibitory actions of CSPGs. To modulate proteoglycan-mediated inhibition over large regions, the Ohio-based researchers used systemic agents that could block interactions with this receptor in the presence of any evolving lesion without the need to impale the CNS parenchyma directly.
The researchers turned to intracellular sigma peptide (ISP), a peptide mimetic of the PTPσ regulatory, wedge region capable of CNS penetration. Along these lines, systemic delivery of ISP has been shown to rapidly enter the CNS and promote significant axonal sprouting with restored sensory-motor and bladder function after acute contusive cord injury in adult rats.
NervGen, a pharmaceutical startup company, licensed from CWRU an issued patent (#9937242) covering the ISP to generate NVG-291-R. Post-stroke treatment with NVG-291-R results in increased axonal sprouting and neuroblast migration deeply into the lesion scar with a transcriptional signature reflective of repair.
Jerry Silver, PhD, co-author of the study, professor of neurosciences at CWRU’s School of Medicine, and an advisor to the startup pharmaceutical company NervGen, said the study showed the drug repaired damage through at least two avenues: creating new neuronal connections and enhancing the migration of newly born neurons derived from neuronal stem cells to the site of the damage.
“NVG-291-R’s ability to enhance plasticity was demonstrated by using staining techniques that clearly showed an increase in axonal sprouting to the damaged part of the brain,” Silver said. “This enhanced plasticity is an excellent validation of the same powerful mechanisms that we and other researchers were able to demonstrate using NVG-291-R in spinal cord injury.”
There are currently no medications approved by the FDA to heal stroke-related damage. NVG-291-R, which is undergoing a Phase I clinical trial in healthy human subjects and is getting ready to start a Phase Ib/II clinical trial for the healing of nervous system damage from spinal cord injury, Alzheimer’s disease, and multiple sclerosis, is owned exclusively by NervGen.