Ohashi Toya
Department of Gene Therapy, Institute of DNA Medicine, The Jikei University School of Medicine, Tokyo, Japan.
Pediatr Endocrinol Rev. 2012 Oct;10 Suppl 1:26-34.
Enzyme replacement therapy (ERT) has been approved for 6 lysosomal storage diseases (LSDs) worldwide including Japan. These diseases include Gaucher disease (GD), Fabry disease, mucopolysaccharidosis (MPS) types I, II, and VI, and Pompe disease (PD). The efficacy and safety of ERT for LSDs has been confirmed by extensive clinical trials. However, there are still obstacles to successful ERT, such as immune reactions against the infused enzyme, mistargeting of enzymes rather than lysosomes, and intractable tissues. Regarding immune reactions, a negative impact of antibody formation on therapeutic effect has been reported for GD, Fabry disease, MPS type I, and PD. In PD, mistargeting of the enzyme was reported in a mouse model due to autophagic build up. Another challenge is intractable tissues, such as the brain and bone, which are key tissues in LSDs. Thus, control of immune reactions against therapeutic enzymes and control of autophagic build up are key issues to maximize the efficacy of ERT. Finally, the development of a new enzyme that effectively targets the brain and bone is very important to improve the quality of life of patients with LSDs.
酶替代疗法（ERT）已在全球范围内（包括日本）被批准用于6种溶酶体贮积症（LSD）。这些疾病包括戈谢病（GD）、法布里病、I型、II型和VI型黏多糖贮积症（MPS）以及庞贝病（PD）。ERT对LSD的疗效和安全性已通过广泛的临床试验得到证实。然而，ERT成功应用仍存在障碍，如针对注入酶的免疫反应、酶而非溶酶体的靶向错误以及难治性组织。关于免疫反应，已报道抗体形成对GD、法布里病、I型MPS和PD的治疗效果有负面影响。在PD中，由于自噬积累，在小鼠模型中报道了酶的靶向错误。另一个挑战是难治性组织，如大脑和骨骼，它们是LSD中的关键组织。因此，控制针对治疗性酶的免疫反应和控制自噬积累是最大化ERT疗效的关键问题。最后，开发一种能有效靶向大脑和骨骼的新酶对于提高LSD患者的生活质量非常重要。
