The gene therapy for hypophosphatasia animal model

2018 Fiscal Year Final Research Report

• Project/Area Number: 15K09605
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Nippon Medical School
• Principal Investigator: Matsumoto Tae 日本医科大学, 医学部, 助教 (10366742)
• Co-Investigator(Kenkyū-buntansha): 三宅 弘一 日本医科大学, 医学部, 准教授 (90267211)
• Project Period (FY): 2015-04-01 – 2019-03-31
• Keywords: 低ホスファターゼ血症 / アルカリホスファターゼ / 遺伝子治療 / AAVベクター

Outline of Final Research Achievements

Hypophosphatasia is an inherited skeletal disease characterized by defective bone and teeth mineralization due to the deficiency of tissue-nonspecific alkaline phosphatase (TNALP), which leads to abnormal mineralization of skeletal and dental tissues. TNALP knockout (Akp2-/-) mice are good models for infantile HPP.We used a single intramuscular injection of Adeno associated vector type 8 (AAV8)with a bone-targeted form of human TNALP in which a deca-aspartate sequence is linked to the C terminal end of soluble TNALP (TNALP-D10) to prolong Akp2-/- mice life with insufficient bone maturity.Treated Akp2-/- mice with AAV8-TNALP-D10 lived longer than 1 year with normal physical activity and healthy appearance, while control Akp2-/- mice died in 3 weeks. At 18 months, bone mineral density and bone volume/tissue volume values were close to those of control ones. The success of intramuscular gene therapy for Akp2-/- mice with AAV8-TNALP-D10 shows possibility to achieve human therapy.

Free Research Field

小児医学

Academic Significance and Societal Importance of the Research Achievements

低ホスファターゼ血症はヒトでは多様な重症度を示し、重症型では骨形成が不十分で胸郭の形態が維持されず呼吸不全で出生後早期に死亡することもあるが、軽症でも乳歯脱落のため義歯が必要であったり骨折をおこしやすく、生活の質がさがりやすい。単一遺伝子の異常によりおこるアルカリホスファターゼ酵素欠損による疾患であり、遺伝子治療で、体内でアルカリホスファターゼ産生ができるようになれば治療意義が大きい。
AAV8-TNALP-D10 ベクターの筋肉注射での治療成功は、ただ一回のベクター局所投与でのヒトでの治療可能性を示した、臨床応用に大きな一歩と言える。