講演情報
[O33-3]低ホスファターゼ症に対する新規治療（遺伝子治療薬:ARU-2801）の開発
○松本 多絵1,2, 三宅 紀子3, 趙 東威2, Mohammad Shadid4, Eric Gaukel5, 成澤 園子6, Jose Millan6, 三宅 弘一2 (1.日本医科大学小児科学教室, 2.日本医科大学遺伝子治療学, 3.日本医科大学生化学・分子生物学（分子遺伝学）, 4.Aruvant Sciences, Burligton, MA, USA, 5.Roivant Sciences, NC, USA, 6.Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA)
Hypophosphatasia (HPP) is an inherited bone disease caused by a deficiency of tissue-nonspecific alkaline phosphatase (TNAP). Enzyme replacement therapy requires subcutaneous injection 3-6 times a week for the rest of the patient‘s life. We evaluated the efficacy and safety of a gene therapy drug (TNAP-expressing type 8 adeno-associated virus vector; ARU-2801) to develop an alternative treatment. ARU-2801 [1.0x1011, 3.0x1011, 1.0x1012 vector genomes(vg)/body] was injected intramuscularly once during the neonatal period (P1-3) to Alpl -/- mice, and survival, improvement of bone formation and plasma alkaline phosphatase (ALP) activity were investigated for 18 months. In Non-human primates (NHPs), ARU-2801 was injected once intramuscularly at 1.0 x1013 vg/body and evaluated the safety for up to 84 days. All untreated Alpl -/- mice (n=4) died within 1 month. Over 3.0x1011 vg treated Alpl -/- mice (n=14) maintained high plasma ALP activity around 10,000 U/L and showed prolonged survival. Alpl -/- mice in the 1.0x1012 vg group (n=7) exhibited weight gain, and bone mineral density as well as wild-type mice. The treated Alpl -/- mice showed no abnormal blood chemistry tests, and no tumor formation or ectopic calcification. The treated NHPs also showed sustained plasma ALP activity with no toxicities. Thus, ARU-2801 was effective and safe in both Alpl -/- mice and NHPs. ARU-2801 could be a potentially life-prolonging and quality-of-life-improving agent for HPP patients that warrants further development as a novel treatment alternative to current enzyme replacement therapy.