Biodegradable delivery system containing a peptide inhibitor of polyglutamine aggregation: a step toward therapeutic development in Huntington's disease

Huntington's and eight other neurodegenerative diseases occur because of CAG repeat expansion mutation culminating into an expanded polyglutamine tract in respective protein. In Huntington's disease (HD), a number of CAG repeats beyond normal repeat length (>36) lead to the formation of mutant protein, the proteolytic cleavage of which induces aggregation in polyglutamine length-dependent manner. The neurodegeneration in this disease is linked to aggregation, and its inhibition is a potential approach for therapeutic development. Although peptides and other molecules have been developed for inhibiting aggregation, peptides in general are susceptible to degradation in vivo conditions. To understand their clinical significance, they also need to be delivered through blood-brain barrier. Here, for the first time, we have synthesized poly-D,L-lactide-co-glycolide nanoparticles containing a polyglutamine aggregation inhibitor peptide PGQ(9)[P-2], by nanoprecipitation method. This process yielded less than 200nm spherical nanoparticles with uniform distribution. Characterization studies by infrared spectroscopy-based and HPLC-based assays show the presence of PGQ(9)[P-2] in nanoparticles. In vitro release kinetics demonstrates that nanoparticles release PGQ(9)[P-2] by erosion and diffusion processes. When the PGQ(9)[P-2]-loaded nanoparticles are incubated with aggregation-prone Q(35)P(10) peptide, representing N-terminal part of Huntingtin protein, it arrests the elongation phase of Q(35)P(10) aggregation. These findings propose the first step toward delivery of a peptide inhibitor against polyglutamine aggregation in HD. Copyright (C) 2014 European Peptide Society and John Wiley & Sons, Ltd.