A systemically injectable peptide, which may make it possible to restore lost functions in spinal cord injury patients, is moving toward clinical trials in early 2020.
The treatment, which was developed by Jerry Silver, a professor of neurosciences at Case Western Reserve University’s School of Medicine and advisor for NervGen Pharma, is the culmination of decades of work, and in pre-clinical studies, it has shown robust results in animal models.
Silver’s research has focused on why nerves are unable to regenerate. One key discovery, made 30 years ago, involved the critical role of a family of molecules called proteoglycans in nerve injury. During development of the brain and spinal cord, proteoglycans normally bind a receptor known as protein tyrosine phosphatase sigma (PTPσ) to help form proper synapses between neurons. Upon nerve injury, proteoglycans reappear within the scar, but because the severed nerve fibers make more of this same sticky receptor, they become forever entrapped within the scar, keeping them from regenerating. Silver hopes spinal cord injuries can be treated by overcoming these abnormal interactions between proteoglycans and the PTPσ receptor.
“You can think of the scar as flypaper to all cell types that have the receptor,” said Silver. “The job of the scar is to create a bandage around the lesion, but in doing so it blocks regeneration.”
The scar is important to wall off inflammation, so instead of trying to get rid of the scar, Silver’s work focused on allowing cells to free themselves from it. To do this, Silver’s lab developed Intracellular Sigma Peptide (ISP), which blocks PTPσ. With PTPσ blocked, cells with this receptor no longer see the proteoglycans, allowing them to regenerate the nerve fibers at the site of damage.
Pre-clinical studies in rats have shown significant recoveries, with every animal showing improved bladder function and more than a third of animals regaining their ability to walk. This work has been independently replicated with an increased dosage, which showed even better recovery. Silver has also recently published results targeting the same signaling pathway that may provide similar promise for chronic spinal cord injury patients.
Silver advises NervGen Pharma, which is working to bring NVG-291 –a close analog of ISP used by Silver’s lab – into the clinic. The Phase 1 clinical trial is expected to open in early 2020 and will test safety and dosing.
While the current focus of NVG-291 is on spinal cord injuries, the applications may be much broader. If results from clinical trials involving NVG-291 are successful for spinal cord injury patients, the peptide might also be beneficial in treating several other debilitating conditions.
“The scar blocks growth in heart attacks after peripheral nerve injury or stroke, and in diseases such as multiple sclerosis and Alzheimer’s disease,” said Silver.
Silver said the ISP in animal models showed no evidence of side effects such as pain or impaired mobility over the course of their treatment.
While spinal cord injury patients will continue to need physical rehabilitation, the hope is that clinical trials will show that NVG-291 can improve the debilitating prognosis associated with this kind of injury.
Almost 200,000 Americans have spinal cord injuries, with an estimated 17,000 new injuries each year. More than a million Americans have a debilitating peripheral nerve injury, and many others experience additional issues related to nerve damage and tissue scarring.
By Gaius J. Augustus