Jarnes Jeanine R, Pillai Nishitha R, Ahmed Alia, Shrestha Sofia, Stark Molly, Whitley Chester B
Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA.
Advanced Therapies Program, University of Minnesota, Fairview, Minneapolis, MN, USA.
Mol Genet Metab Rep. 2024 Dec 17;42:101179. doi: 10.1016/j.ymgmr.2024.101179. eCollection 2025 Mar.
The current standard of care for infantile-onset Pompe disease (IOPD), a severe form of acid α-glucosidase enzyme activity deficiency is: (1) detection by newborn screening, (2) early initiation of intravenous enzyme replacement therapy (ERT) using recombinant human acid alpha-glucosidase (rhGAA), with higher doses of rhGAA increasingly used to improve clinical outcomes, and (3) immune tolerization induction (ITI) using to prevent anti-rhGAA antibody formation, with methotrexate (MTX), rituximab, and IVIG used for patients who are cross-reactive immunologic material negative (CRIM-) and monotherapy with MTX used in patients who are cross-reactive immunologic material positive (CRIM+).
OBJECTIVES/METHODS: A pilot study evaluates a dose-intensive therapy (DIT) using high-dose ERT (40 mg/kg/week) and more frequent exposure to ERT (i.e., 3 times weekly administration) to mitigate anti-rhGAA antibody formation, as an alternative to the standard therapeutic approach for IOPD.
In the first patient, DIT resulted in rapid normalization of the following: (1) bi-ventricular hypertrophy, (2) urine HEX-4, (3) CK, (4) liver transaminases. At 7 years of age, the patient continues the DIT regimen. To date, all pediatric developmental milestones have been met on time, anti-rhGAA antibodies have been negative and the patient is able to attend school and maintain normal activities of daily living.
Over a 7-year period, DIT for CRIM-positive IOPD was well tolerated in the first patient treated. Excellent clinical outcomes were achieved, and anti-rhGAA antibodies levels were consistently undetectable. Assessments of more patients, that includes patients with CRIM-, as well as CRIM+ IOPD, will determine if this approach consistently achieves improved clinical outcomes and immune tolerization.
婴儿型庞贝病（IOPD）是一种严重的酸性α-葡萄糖苷酶活性缺乏症，目前的标准治疗方案为：（1）通过新生儿筛查进行检测；（2）早期开始使用重组人酸性α-葡萄糖苷酶（rhGAA）进行静脉酶替代疗法（ERT），越来越高剂量的rhGAA被用于改善临床结局；（3）使用免疫耐受诱导（ITI）来预防抗rhGAA抗体的形成，对于交叉反应性免疫物质阴性（CRIM-）的患者使用甲氨蝶呤（MTX）、利妥昔单抗和静脉注射免疫球蛋白（IVIG），对于交叉反应性免疫物质阳性（CRIM+）的患者使用MTX单药治疗。
目的/方法：一项试点研究评估了一种剂量强化疗法（DIT），即使用高剂量ERT（40mg/kg/周）并更频繁地接受ERT（即每周给药3次）以减轻抗rhGAA抗体的形成，作为IOPD标准治疗方法的替代方案。
在首例患者中，DIT使以下各项迅速恢复正常：（1）双心室肥厚；（2）尿HEX-4；（3）肌酸激酶（CK）；（4）肝转氨酶。该患者7岁时继续接受DIT方案治疗。迄今为止，所有儿童发育里程碑均按时达成，抗rhGAA抗体呈阴性，患者能够上学并维持正常的日常生活活动。
在7年期间，首例接受治疗的CRIM阳性IOPD患者对DIT耐受性良好。取得了优异的临床结局，且抗rhGAA抗体水平始终未检测到。对更多患者（包括CRIM阴性以及CRIM阳性IOPD患者）的评估将确定该方法是否始终能实现更好的临床结局和免疫耐受。
