Chapter 17: A New Generation of Noninvasive NGF-Based Therapies for Alzheimer's Disease Check Access

Converging evidence indicates Nerve Growth Factor as a potential disease-modifying therapeutic protein for Alzheimer's Disease. New evidence has demonstrated a direct link between defects in NGF signalling, processing or transport to the aberrant activation of AD neurodegeneration, further reinforcing the strong rationale for NGF as a therapeutical candidate for AD.

However, the development of an NGF-based therapy for AD has remained a considerable challenge, due to limited access of NGF to the brain, across the blood brain barrier, and to the potent physiological nociceptive action of NGF itself. While the non invasive delivery of NGF to the brain has found a viable solution in the intranasal delivery route, the potent physiological pro-nociceptive activity of NGF is a problem that remains to be solved, for a therapeutical development of NGF in AD, as it has proven to be severely dose-limiting in previous large human clinical trials in which recombinant NGF was being tested for diabetic polyneuropathies. In this chapter we review the strong rationale and the problems for the therapeutical development of NGF in AD, and we describe new work on variants of NGF that represent a new generation of NGF-based therapeutical candidates. These molecules have the property of being traceable, with respect to endogenous NGF, thus facilitating the careful dosing in vivo, required to meet the therapeutical window.

Moreover, we were inspired by a missense point mutation (C661T, leading to the aminoacid substitution R100W) that was recently described in the NGFB gene of individuals affected by a rare form of hereditary loss of pain perception (Hereditary Sensory and Autonomic Neuropathy type V, HSANV), to engineer variants of NGF that are unable to activate the nociceptive pathways in sensory neurons, while maintaining identical neurotrophic and anti-amyloidogenic properties in central neurons. The R100W mutation abolishes the binding of NGF to p75^NTR receptors and alters the signalling pathways activated downstream of TrkA receptors, providing a rational basis for the development of “painless” hNGF variants as a new generation of therapeutics for neurodegenerative diseases.