Small peptide fragments of neuronal growth factors are a promising neuroprotective strategy. Joseph Harding (M3 Biotechnology, Seattle, WA, USA) described the development of dihexia, a novel blood–brain barrier (BBB)-permeable hepatocyte growth factor mimetic derived from angiotensin IV. Dihexia potentiates the activity of hepatocyte growth factor at the tyrosine kinase receptor, cMet, rescuing behavioral deficits in a scopolamine model and in a Parkinson’s disease lesion model. Antonio Catteneo (Scuola Normale Superiore, Pisa, Italy) demonstrated that intranasal administration of human nerve growth factor (hNGF P61S/R100E) rescued cognitive deficits, reduced amyloid plaque load and size, and lowered amyloid-beta (Aβ) levels without causing hyperalgesia in the APP/PS1 mouse model. Khalid Iqbal (New York State Institute for Basic Research, New York City, NY, USA) discussed peptide-6, a peptide fragment of the ciliary neurotrophic factor that decreased Aβ and phospho-tau in a mouse model of AD.
Paolo Pevarello (Axxam SpA, Milan, Italy) discussed a small-molecule approach to target neuroinflammation through modulation of microglial ligand-gated receptor P2X7, which is required for microglial activation by Aβ [1]. While P2X7 antagonists are used in the clinic for rheumatoid arthritis, Pevarello presented lead optimization data for novel compounds that are central nervous system penetrant. John Schetz (University of North Texas Health Science Center, Fort Worth, TX, USA) presented lead optimization data for modulators of sigma-1 receptor. Activation of sigma-1 receptor selectively inhibits inducible nitric oxide synthase activity at sites of inflammation. Seema Briyal (Midwestern University, Downers Grove, IL, USA) discussed a preclinical program targeting the endothelin-B receptor, expressed by both endothelial cells and astrocytes. IRL-1620, a novel endothelin-B receptor agonist, increased expression of vascular endothelial growth factor receptor and nerve growth factor to stimulate angiogenesis and neurogenesis in an ischemic rat model.
To compensate for transcriptional shifts that have been described in several neurodegenerative diseases, Tamara Maes (Oryzon Genomics, Barcelona, Spain) presented the rationale for ORY-2001, a new BBB-permeable, histone demethylase LSD1/monoamine oxidase-B inhibitor. ORY-2001 restored behavioral deficits and protein levels of ubiquitin carboxyl-terminal esterase L1 (UCHL1) and Notch1 in the SAMP8 mouse model of accelerated senescence. The Oryzon dual LSD1/monoamine oxidase-B inhibitor is ready for pre-investigational new drug-enabling studies for AD.
Lawrence Wennogle (Intra-cellular Therapies, Inc., New York, NY, USA) described the development of novel therapeutics that target overexpression of casein kinase-1, a circadian rhythm protein that may cause sleep disruption in AD patients, and has been linked to enhanced Aβ production and tau phosphorylation. Intra-cellular Therapies, Inc., has identified selective, BBB-permeable lead casein kinase-1 inhibitors that decrease hyperlocomotion in a casein kinase-1-overexpressing mouse model, and may have therapeutic potential for AD.