第19巻 2023年8月　第3号

■特集〔遺伝子治療update：日本医科大学の遺伝子治療研究（7）〕

低ホスファターゼ症モデルマウスにおける遺伝子治療―臨床応用にむけて―
松本　多絵
日本医科大学多摩永山病院小児科
日本医科大学遺伝子治療学

Gene Therapy for Hypophosphatasia in Alpl^—/— mice (infantile HPP model) -Toward Clinical Application
Tae Matsumoto
Department of Pediatrics, Nippon Medical School Tama Nagayama Hospital
Department of Gene Therapy, Nippon Medical School

Hypophosphatasia (HPP) is an inherited bone disease resulting from a deficiency of tissue-nonspecific alkaline phosphatase (TNALP). It is fatal in its severe perinatal and infantile forms. Asfotase alfa (Strensiq^®) is an approved enzyme replacement therapy for HPP. It's use requires injections 3-6 times per week for all of the patient's life. Therefore, although this treatment is effective, it is also burdensome. We investigated the efficacy and safety of a gene therapy drug (TNALP-D10-expressing type 8 adeno-associated virus vector: ARU-2801) administered intramuscularly to Alpl ^—/— mice (infantile HPP model) and non-human primates with the aim of developing a less burdensome treatment. After administration of 3.0×10¹¹ vg/body (n=4/7) or 1.0×10¹² vg/body (n=5/7) ARU-2801, treated mice maintained high plasma ALP activity and exhibited body weight gain and bone maturity similar to wild-type mice throughout their survival period, which was up to 18 months. Biodistribution of ARU-2801 was detected only in the intramuscular region on the administration side. There were no tumors or ectopic calcification detected at autopsy or histopathological examination. After administration of 1.0×10¹³ vg/body ARU-2801 to juvenile macaque monkeys, durable high plasma ALP levels were sustained for up to 38 weeks with no biochemical abnormalities detected in the blood. Radiological and histopathological examinations also showed no abnormality. The clinical chemistry parameters for ARU-2801-treated mice and macaques indicated that plasma ALP activity is maintained with no toxicities at levels that are potentially clinically efficacious. Thus, ARU-2801, which can be administered as a single dose, has the potential to improve the quality of life of HPP patients by eliminating the need for indefinitely repeated injections.

日医大医会誌 2023; 19(3), 229-234

Key words
hypophosphatasia, muscle injection, neonatal gene therapy, adeno-associated virus vector, tissue-nonspecific alkaline phosphatase

Correspondence to
Tae Matsumoto, Department of Pediatrics, Department of Gene Therapy, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan
E-mail：tae@nms.ac.jp

受付：2023年4月24日　受理：2023年7月3日