Proneurotrophins as Targets for Treatments for CNS Trauma

The p75 neurotrophin receptor is a member of the TNF receptor superfamily. It has been known to activate inflammatory and apoptotic pathways, as well as some cell survival pathways. Until recently, the only known ligands for p75 were mature neurotrophins, which bind the receptor weakly.

Dr. Barbara Hempstead and her team at Cornell recently identified the proform of the neurotrophins as the high-affinity ligand for p75 (published in Science), and in the course of doing so, created novel, cleavage-resistant proneurotrophins. With a team from Denmark led by Dr. Anders Nykjaer, Dr. Hempstead's group also identified the vps10-domain containing family (including sortilin, sorCS2, sorLA) as a crucial third member of this complex (published in Nature). When assembled, the proneurotrophin/p75/vps10-protein complex activates apoptotic pathways.

The target-system has been validated with small molecules that block sortilin, polyclonal antibodies to the pro-domain, a p75 gene knockout mouse, antibodies blocking p75, proneurotrophin knockin animals, and most recently, off-patent drugs that modulate proneurotrophin uptake. Other labs have knocked out p75 using antisense with promising cell-sparing results, and there is evidence that modulating proteases might be effective as well, as they cleave the proneurotrophins into their mature form.

In the context of inflammation, all three elements of the proNGF apoptotic complex are upregulated in acute neural damage (proNGF is found secreted in the CSF, while p75 and sortilin are found on neural membranes), and blocking the binding of proNGF in mouse and rat models of spinal injury rescued more than 90% of neurons in the penumbra from cascading apoptosis (2004 PNAS). This signalling system is also involved in the spread of cancers of neuro-ectodermal origin, such as melanoma and glioblastoma.

Unlike proNGF, proBDNF has recently been found to play a role in normal physiology, especially in the brain, where research from the lab of Bai Lu at the NIH, in collaboration with the Hempstead lab, has shown it is a key switch in determining whether a synapse is strengthened or weakened. Work is underway to explore the role of the proBDNF/p76/vps10-domain-proteins in other systems as well.

The Hempstead lab has developed high-throughput cell-based screens to identify modulators of proneurotrophin uptake, as well as secondary assays to validate hits.

Potential Commercial Applications

• Acute CNS trauma, such as stroke, brain injury, and spinal cord injury
• Chronic neurodegenerative diseases, including Alzheimers
• Melanoma, glioblastoma
• Psychiatric disorders
• Memory disorders