Finely-tuned carrier design for improved gene therapy

26-Jun-2015 - Japan

There is much interest in messenger RNA (mRNA) as a potential candidate for nucleic acids drug. However, the very labile nature of mRNA has hindered its clinical applications. Polyion complex formed from mRNA and polycations, which is termed ‘Polyplex’, can protect mRNA from enzymatic degradation and enhance its cellular uptake. Fine-tuning of the chemical structure of polycations dramatically improve the ability of polyplex to deliver mRNA.

Prof. Kazunori Kataoka and co-workers at the University of Tokyo synthesized the polyaspartamides possessing the different number of aminoethylene repeats in their side chain. By applying the polyaspartamides for mRNA carriers, they found that the polyaspartamides possessing odd number of aminoethylene repeats (PA-Os) provided more persistent protein expression compared with those possessing even number repeats (PA-Es).

Prof. Kataoka and his team also revealed that, despite lower capacity of endosomal escape than PA-Es, the carriers composed of PA-Os had high stability in the cytoplasm allowing retention of mRNA stably inside the carriers. Eventually, PA-Os can provide protein expression in a long and sustained manner. These feature are in sharp contrast to the case of DNA delivery, where PA-Es exhibited high capacity due to the facilitated endosomal escape.

The researchers concluded that the sophisticated molecular design of carriers is important for realizing clinical application using nucleic acids drugs.

Original publication

Hirokuni Uchida, Keiji Itaka, Takahiro Nomoto, Takehiko Ishii, Tomoya Suma,∥ Masaru Ikegami, et al. "Modulated protonation of side chain aminoethylene repeats in N‑substituted polyaspartamides promotes mRNA transfection."; The Journal of the American Chemical Society 136 (2014).

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