Nanomachines with wine ingredients overcome the challenges of gene therapy

Researchers will be the first in the world to use mice to overcome the key challenges of gene therapy using adeno-associated viral vectors (AAVs), particularly “producing neutralizing antibodies” and “hepatotoxicity.” I demonstrated my ability. Nanomatin equipped with AAV.

The findings are published in the Journal ACS Nano.

The co-first author of this paper is Assistant Professor Uto Honda at the Institute of Chemistry and Life Sciences at the Tokyo Institute of Science. Dr. Hiroaki Kino and Professor Nishiyama, the leading research scientists at ICONM, are listed as corresponding authors alongside Professor Honda, while other researchers at ICONM are recognized as co-authors.

The researchers designed nanomatins equipped with adeno-associated viral vectors (AAVs) by combining precise synthetic polymers made from tannic acid and phenylboronic acid, components found in wine and tea. Using this approach, they successfully overcome the challenges of “decreasing gene transfer efficiency due to hepatotoxicity caused by liver accumulation” and “decreasing hepatotoxicity” in mice for the first time in the world.

Although AAV is clinically applied as a gene therapy vector, patients who neutralize antibodies to AAV do not achieve sufficient gene transfer efficiency, limiting the therapeutic population and the possibility of multiple administrations. It is known. The researchers focused on the properties of tannic acid, a natural ingredient found in wine and other sources, to easily attach biomolecules.

By combining it with a precise synthetic polymer made from phenylboronic acid, they developed new AAV equipped nanomatins.

This AAV-equipped nanomatin demonstrates sufficient gene transfer activity even in the presence of AAV neutralizing antibodies, and has also been shown to suppress the increase in liver toxicity markers caused by AAV9 by inhibiting liver AAV accumulation. Ta.

Furthermore, this nanomatin exhibits gene transfer efficiency in the central nervous system comparable to that of AAV alone, indicating the potential for important gene therapy effects.

Findings from this study are expected to be applied as a novel therapeutic approach to viral vector therapy and are currently limited by neutralizing antibodies.

To avoid neutralizing antibodies from AAV, the research group developed AAV-equipped nanomatins by combining tannic acid with a precision synthetic polymer.

Tannic acid, a type of polyphenol found abundantly in wine and tea, interacts with biomolecules such as proteins and viral vectors through hydrophobic interactions and hydrogen bonds to form complexes. Furthermore, tannic acid is a natural ingredient that has attracted attention as a pharmaceutical ingredient due to its excellent biodegradability and biocompatibility.

Focusing on these excellent properties of tannic acids, Honda and colleagues have previously reported on biomolecular delivery nanomatins combined with precision similar polymers containing phenylboronic acids that form tannic acids and esters with tannic acids. Masu.

This nanomatin can be easily formed by simply mixing the desired molecule with a tannic acid and a precision-sindified polymer in water, releasing loading molecules at the acidic pH found in the cells, showing sufficient activity.

The research group aimed to load AAV into the nanomatin and tackle treatment (neutralizing antibodies, hepatotoxicity) without compromising the activity of AAV. When AAV serotype 9 (AAV9) was administered systemically to mice with AAV neutralizing antibodies, brain and liver transgenic efficiency was reduced to 5-15%.

However, loading AAV9 into nanomatins increased the brain and liver gene transfer efficiency during systemic administration to approximately 50-60%, significantly reducing the loss of activity compared to AAV9 alone. Furthermore, the nanomachine limited the effect on the liver to less than 10%, effectively suppressing the hepatotoxicity associated with high-dose AAV9 administration.

In this way, not only overcomes the challenges of gene therapy viruses, but also demonstrates the brain transduction efficiency of AAV9 alone, addressing the problems posed by conventional delivery carriers that reduce AAV activity, and thus substantially Dealing with gene therapy effects. It’s expected.

Furthermore, by combining microbubbles with intensive ultrasound irradiation, this study successfully enhanced the selectivity of gene transfer to the brain by six times.