5pm on June 26, 2020 - Kawasaki/Japan: The Innovation Center of NanoMedicine (iCONM), the National Institute for Quantum Science and Technology (QST), and the University of Tokyo jointly announced that a reagent for the selective and safe coating of the liver sinusoidal walls to control the clearance of gene therapy drugs was successfully developed. The contents of this research will be published in Science Advances by the American Association for the Advancement of Science (AAAS) at 2:00 pm on June 26, east coast of the United States (Japan standard time: 3:00 am on 27th): A. Dirisala, S. Uchida, K. Toh, J. Li, S. Osawa, T. A. Tockary, X. Liu, S. Abbasi, K. Hayashi, Y. Mochida, S. Fukushima, H. Kinoh, K. Osada, Kazunori Kataoka, "Transient stealth coating of liver sinusoidal wall by anchoring two-armed PEG for retargeting nanomedicines".

Recently, gene therapies have been successively approved in Europe, US, and Japan, and are expected to provide novel therapeutic options for cancer, chronic diseases, acquired and inherited genetic disorders. Whilst this is promising, in reality, when gene therapy drugs are systemically administered to living organisms, they are rapidly eliminated and metabolized in the liver, thus impeding the delivery of a sufficient amount to the target organs and raising the toxicity concerns. This elimination by the liver is caused by the adsorption of the gene therapy drugs to the vascular wall of the liver sinusoid, which is an intrahepatic capillary. To overcome this issue, we conceived to selectively coat the liver sinusoidal wall using polyethylene glycol (PEG). However, a long-term coating may impair the normal physiological functions of the liver, and therefore the coating should be transient. In addition, coating needs to be selective for liver sinusoids, as coating the blood vessels throughout the body would not only cause adverse effects but also decrease the delivery amount of gene therapy drugs to target organs. Towards this end, we have developed a coating agent with two-armed PEG conjugated to positively charged oligolysine, which demonstrated the selective coating on the liver sinusoidal wall, the first-of-its-kind strategy in the world. Interestingly, the coating with two-armed PEG was excreted into bile within 6 hours after binding to sinusoidal walls, while the coating with single chain of linear PEG bound to oligolysine persisted in the walls for a long time. In this way, the precise molecular design was necessary to achieve a transient coating.

This coating was subsequently applied to boost the delivery efficacy of gene therapy drugs. Adeno-associated virus (AAV) is widely used for viral gene therapy drugs, and its serotype 8 (AAV8) targets myocardium and skeletal muscles. When AAV8 was administered after prior coating of two-armed PEG to the liver sinusoidal wall, the transfer of AAV8 to the liver was suppressed, and as a result, the gene transfer efficiency into the myocardium and skeletal muscles was improved by 2 to 4 times. This approach is promising for the treatment of muscular dystrophy. In addition, we expanded the use of our strategy to virus-free gene delivery systems, which allows more economically attractive and safe gene therapy. We have been working on non-viral gene therapy for malignant tumors using plasmid DNA-equipped smart nanomachine for over 10 years. When the coating agent was used for this system, the adsorption of nanomachines to the sinusoidal wall was suppressed, resulting in an approximately 10-fold improvement in DNA transfer efficiency to colon cancer. As described above, we have succeeded in boosting the activity of gene therapy drugs while ensuring safety by using the coating agent developed this time.

The above findings are summarized as follows:

- The coating agent with two-armed PEG selectively coated the liver sinusoid wall for several hours and was then excreted in the bile.

- The coating agent with single chain of linear PEG is not excreted in bile and coated the liver sinusoidal wall for more than 9 hours, which raises a safety concern.

- The coating agent with two-armed PEG had selectivity for the liver sinusoid wall, without coating the blood vessels in the connective tissues.

- The coating agent improved the gene transfer efficacy to the myocardium and skeletal muscles using the AAV vector by 2 to 4 times, and the gene transfer efficiency to colorectal cancer using DNA-loaded smart nanomachines by 10 times.

- As a result, our approach is expected to allow for improving the effect of gene therapy drugs and reducing their dose needed to obtain therapeutic outcome, which will lead to the reduction of medical cost and adverse event opportunities.

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Development of safe liver sinusoid coating agents to increase the efficacy of gene therapy - Science Codex