Gene Therapy for Hypophosphatasia in <i>Alpl</i>^−/− mice (infantile HPP model) -Toward Clinical Application

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.