“Targeting Toxic Proteins: Novel Drug Approaches to Defeat Dementias” in Genetic Engineering and Biotechnology News (December 16, 2016) discusses the challenges posed by the complex pathogenesis of Alzheimer’s disease (AD) and other related diseases to treatment approaches. Because of my research background in protein folding and degradation, I am particularly interested in disorders, such as AD, that stem from misfolding and/or aggregation of proteins.
Despite many years of research, treatment options for AD remain limited. Lack of efficacy have resulted in termination of a large number of clinical trials for AD, as exemplified by the recent failure of Eli Lilly’s solanezumab in a Phase 3 trial. While most therapeutic approaches so far have been targeting one type of protein, it may be worthwhile to consider a different strategy that aims at a broader set of targets.
The pathogenesis of AD and related disorders is rooted in the aggregation of neuronal proteins inside and outside of cells due to factors such as advanced age and genetic abnormalities, leading to clinical symptoms of disease. One such protein is the misfolded and self-oligomerizing amyloid-β peptide (Aβ), which subsequently disrupts neuronal function in addition to affecting a diverse range of key cellular processes including proteasomal and mitochondrial functions. Therapies, e.g., solanezumab and crenezumab, that failed to meet primary endpoints at clinical trials targeted Aβ, but lacked specificity. Proclara Biosciences (Cambridge, MA)’s general amyloid interaction motif (GAIM) technology uses a different approach by simultaneously targeting several misfolded proteins instead of just one protein, potentially allowing for broader treatment. Their candidate molecule, NPT088, is a fusion protein consisting of the active fragment of bacteriophage M13 gene 3 protein (g3p) and the constant region (partial) of human immunoglobulin gamma-1 heavy chain (IgG1-Fc); a Phase 1b trial in patients with mild or moderate AD is ongoing.
The 99% failure rate of new drugs for treating AD over the past decade strongly suggest that approaches besides existing strategies should be considered. With an aging population and the considerably high economic and social costs associated with such debilitating neurological diseases, it may be time to think outside the box.