https://bio.nikkeibp.co.jp/atcl/column/16/031700078/102300034/

Genetically modified crops and foods, 2024 will see movement with the release of fluorescent protein silk and cedar pollen rice

Yoshiko Sasa, Managing Director of the NPO Kurashi to Bio Plaza 21, summarized the trends in the cultivation and regulation of genetically modified crops in Japan. In 2024, a new product made from genetically modified silkworms was released, and there was a long-awaited movement in the development of cedar pollen rice.

The cultivation and breeding status of genetically modified animals and plants in Japan is summarised every year. Based on the Cartagena Protocol, biodiversity impact assessments have been conducted on 17 types of genetically modified crops, including alfalfa and rice, that can be used and cultivated in Japan in a form that does not completely prevent their spread into the environment, known as Type 1 use. Of these, only two have been commercially cultivated in Japan so far:

• one type of rose (approved in 2008) and
• one type of orchid, Phalaenopsis (approved in 2021).

These have been commercialized as Suntory Holdings’ blue rose “APPLAUSE” and Ishihara Sangyo Kaisha’s blue moth orchid “Blue Gene,” respectively.

Genetically modified silkworms have also been produced for the purpose of using them for fiber. From 2023 to the present, test breeding has been conducted at the National Agriculture and Food Research Organization (NARO) and the Gunma Prefectural Sericulture Technology Center. NARO and the center have long been conducting research on genetically modified silkworms as a joint research project, and have also conducted biodiversity impact assessments assuming breeding by general producers. In July 2024, the center began selling cocoons and raw silk from “GFP Gunma 200,” a green fluorescent silk made from silkworms introduced with green fluorescent protein (GFP). In addition to silk with fluorescent proteins, the center is also conducting research on genetically modified silkworms that produce high-performance silk, and is holding local information sessions on breeding. Test breeding of these genetically modified silkworms for practical use have been conducted by the center and NARO in 2024.

In addition, there are various products that have been made using genetically modified silkworms bred in closed systems and released to the market. For genetic modification, silkworms can also be infected with a genetically modified baculovirus that has introduced a target gene. The resulting silkworms are not considered genetically modified organisms, but the genetically modified baculovirus they use is subject to the Cartagena Protocol.

Products from genetically modified silkworms

• 2008 Osteoporosis test agent (Nittobo Medical [Chiyoda, Tokyo; President and CEO: Fukushima Masao])
• 2014 Human collagen I cosmetics (Immuno-Biological Laboratories)
• 2016 Amyloid beta test kit (Immuno-Biological Laboratories)
• 2016 Laminin for culturing iPS cells, etc. (Immuno-Biological Laboratories)
• 2021 Human collagen III cosmetics (Immuno-Biological Laboratories)
• 2023 Plasma fibronectin and cellular fibronectin for scaffolding of cultured cells (Immuno-Biological Laboratories)

Products from the Silkworm baculovirus system

• 1994 Feline interferon (Toray)
• 2005 Canine interferon (Toray)
• 2014 Canine atopic desensitization therapy drug (Nippon Zenyaku Kogyo [Koriyama, Fukushima; President and CEO: Fukui Toshikazu])
• 2017 Blood coagulation reagent (Sysmex)
• 2020 SARS-CoV-2 antibody test kits and various reagents (KAICO [Fukuoka City, CEO Kenta Yamato])
• 2024 sees a long-awaited movement in the development of cedar pollen rice

Among genetically modified crops, cedar pollen rice has been under development since 2000 by the National Agriculture and Food Research Organization. Cedar pollen rice has a fragment of the allergen protein of cedar pollen genetically modified introduced into it. The protein synthesized by genetic recombination accumulates in the protein body of rice endosperm, and it is expected that oral ingestion of it will establish immune tolerance. Two strains have been produced so far: “cedar pollen peptide rice,” which incorporates the gene sequences of seven major epitopes recognized by T cells among cedar pollen allergens, and “cedar pollen polypeptide rice,” which incorporates genes for modified proteins in which the sequences of the two major cedar pollen allergens, Cry j 1 and Cry j 2, are fragmented or shuffled.

In January 2024, the Ministry of Agriculture, Forestry and Fisheries established the “Public-Private Collaboration Study Group for the Practical Use of Cedar Pollen Rice.” The study group put together an “overall picture of hay fever countermeasures” to solve hay fever, including measures over the next 10 years, and released the “Interim Summary for the Practical Use of Cedar Pollen Rice” in June 2024. Clinical research is also being conducted on cedar pollen peptide rice. As a result, although no improvement in clinical symptoms such as rhinitis was observed, a decrease in the proliferation activity of T cells that recognize cedar pollen allergens was observed, and it was said that there is a possibility that immune tolerance to cedar pollen allergens can be induced. In addition, because cedar pollen rice contains antigens that are recognized by T cells, it does not react to IgE antibodies against cedar pollen, and in theory, it is not expected to cause allergic reactions as a side effect.

Initially, it was thought that the rice would be commercialized as a food product in packaged form, but more than 20 years have passed since the idea of ​​whether it should be considered a medicine or a food product was not clarified, and it has still not been put to practical use. Meanwhile, the interim report published in 2024 indicates the following direction:

• Prioritize research into safer “cedar pollen polypeptide rice”
• Conduct additional tests necessary to examine efficacy and safety and clarify the mechanism of action, referring to existing research on immunotherapy drugs for cedar pollen and food allergy treatments
• Draw up appropriate test plans and administer continuously for at least 2-3 years to examine efficacy and safety in order to obtain POC (proof of concept) that shows the usefulness and effectiveness of new drug candidates in humans
• Consider biomarkers that can predict efficacy before or in the early stages of treatment, as it is believed that some cedar pollen allergy patients will not benefit
• Consider risk management measures referring to existing cedar pollen sublingual immunotherapy drugs
• Ensure stable supply of raw rice
• Consider quality control that complies with GMP (good manufacturing practice) When rice is used as a pharmaceutical raw material, it is difficult to control the cultivation process in accordance with GMP, so a dosage form that allows GMP control from the active ingredient extraction process onwards is selected.